The Beclin 1 network regulates autophagy and
R Kang1, HJ Zeh1, MT Lotze*,1and D Tang*,1
Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival,
which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors
(Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP3R, PINK and survivin) to regulate the lipid kinase
Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast,
the BH3 domain of Beclin1is bound to, and inhibitedbyBcl-2or Bcl-XL. This interactioncan bedisrupted by phosphorylation of
Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk
between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and
neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular
homeostasis, focusing on the cross-regulation between apoptosis and autophagy.
Cell Death and Differentiation (2011) 18, 571–580; doi:10.1038/cdd.2010.191; published online 11 February 2011
Autophagy is an essential process that consists of selective
degradation of cellular components. There are at least three
different types of autophagy described and possibly more.
These autophagy types include macroautophagy (hereafter
referred to as autophagy), microautophagy and chaperone-
mediated autophagy.1The initial step of autophagy is the
surrounding and sequestering of cytoplasmic organelles and
proteins within an isolation membrane (phagophore). Poten-
tial sources for the membrane to generate the phagophore
include the Golgi complex, endosomes, the endoplasmic
reticulum (ER), mitochondria and the plasma membrane.2
The nascent membranes are fused at their edges to form
double-membrane vesicles, called autophagosomes. Auto-
phagosomes undergo a stepwise maturation process, includ-
eventually leading to the delivery of cytoplasmic contents to
lysosomal components, where they fuse, then degrade and
are recycled (Figure 1a). The process of mammalian
autophagy is divided into six principal steps: initiation
(Figure 1b), nucleation (Figure 1c), elongation (Figure 1d),
closure, maturation (Figure 1e) and degradation or extrusion.
It has been well demonstrated that autophagy depends on
Atg5/Atg7, is associated with microtubule-associated protein
light chain 3 (LC3) truncation and lipidation, and may originate
directly from the ER membrane and other membrane orga-
nelles. Furthermore, recent study has identified a Atg5/Atg7-
independent pathway of autophagy.3This pathway of auto-
phagy was not associated with LC3 processing but appeared
to involve autophagosome formation from late endosomes
and the trans-Golgi.3Atg7-independent autophagy had been
implicated in mitochondrial clearance from reticulocytes.4The
exact molecular basis of Atg5/Atg7-independent autophagy
remains to be elucidated. Interestingly, Beclin 1 is required for
the presence of Beclin 1-independent autophagy is evaluated
in various experimental setting,5further complicates discern-
ment of the role of these individual pathways.
As a central element signaling cell growth and enhancing
protein translation, the mammalian target of rapamycin
(mTOR), when inhibited, induces autophagy. Moreover, as
a critical feedback mechanism, reactivation of mTOR
terminates autophagy and initiates lysosome reformation
(Figure 1f).6Autophagy principally serves an adaptive, or
as we have termed it, a ‘programmed cell survival’ role
to protect organisms during periods of enhanced cellular
distress. In rare settings, however, the self-cannibalistic
functions, or paradoxically, the pro-survival functions of
autophagy may be deleterious and lead to cell death.
Received 28.10.10; revised 02.12.10; accepted 13.12.10; Edited by H-U Simon; published online 11.2.11
1Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA
*Corresponding author: MT Lotze, Department of Surgery, Hillman Cancer Center, Institute, G.27A, 5115 Centre Avenue, Pittsburgh, PA 15232, USA.
Tel: þ412 623 5977; Fax: þ412 623 1212; E-mail: firstname.lastname@example.org or D Tang, Hillman Cancer Center, G21, 5115 Centre Avenue, Pittsburgh, PA 15232, USA.
Tel: þ412 623 1211; Fax: þ412 623 1212; E-mail email@example.com
Keywords: Beclin 1; PI3K; Bcl-2; autophagy; apoptosis; signal transduction
Abbreviations: Ambra1, activating molecule in Beclin 1-regulated autophagy; BH, Bcl-2-homology; Bif-1, endophilin B1/Bax-interacting factor 1; CCD, coiled-coil
domain; Cdk1, cyclin-dependent kinase 1; DAPK, death-associated protein kinase; ER, endoplasmic reticulum; ECD, evolutionarily conserved domain; ERK,
LC3, microtubule-associated protein light chain 3; mTOR, mammalian target of rapamycin; NES, nuclear export signal; NAF-1, nutrient-deprivation autophagy factor-1;
nPIST, neuronal isoform of protein-interaction, specifically with TC10; NF-kB, nuclear factor-kB; PI3KC3, class III type phosphoinositide 3-kinase; PAS, pre-
autophagosomal structure; PINK1, PTEN-induced putative kinase 1; ROS, reactive oxygen species; RAGE, receptor for advanced glycation end products; Rubicon,
RUN domain protein as Beclin 1 interacting and cysteine-rich containing; TRAF6, tumor necrosis factor receptor-associated factor 6; TP53INP2, tumor protein
Cell Death and Differentiation (2011) 18, 571–580
& 2011 Macmillan Publishers Limited All rights reserved 1350-9047/11
Beclin 1 core complex
Amino acids etc.
Lysosome Lysosome reformation
independent autophagy. (b) The initiation is sustained by activation of ULK1 and ULK2 complexes, which are inhibited by mTOR. (c) The nucleation depends on
Beclin 1-Vps34-Vps15 core complexes and other proteins. (d) The elongation of the phagophore is mediated by two ubiquitin-like conjugation systems that together promote
the assembly of the ATG16L complex and the processing of LC3. PE, phosphatidylethanolamine. (e) The maturation is promoted by LC3, Beclin 1, the lysosomal membrane
proteins LAMP-1 and LAMP-2, the GTP-binding protein RAB7, the ATPase SKD1, the cell skeleton, the pH of lysosomes and possibly presenilin 1 (PS1). (f) Autophagic
lysosome reformation (ALR) cycle. mTOR signaling is inhibited during initiation of autophagy, but reactivated by prolonged starvation. Reactivation of mTOR is autophagy-
dependent and requires the degradation of autolysosomal products. Increased mTOR activity attenuates autophagy and generates proto-lysosomal tubules and vesicles that
extrude from autolysosomes and ultimately mature into functional lysosomes, thereby restoring the full complement of lysosomes in the cell (figure modified from1,6,73,74)
Stages of autophagy. (a) Different types of autophagy. LC3-II is a marker of Atg5/Atg7-dependent autophagy, whereas Rab-9 is a marker of Atg5/Atg7-
Beclin 1 complexes
R Kang et al
Cell Death and Differentiation
The mammalian autophagy gene Beclin 1, an ortholog
of the Atg6/ vacuolar protein sorting (Vps)-30 protein in
yeast, was cloned through a yeast two-hybrid screen in 1998
by Beth Levine’s group.7Beclin 1 is important for localization
of autophagic proteins to a pre-autophagosomal structure
(PAS), depending on interaction with the class III type phos-
form the Beclin 1-Vps34-Vps15 core complex.8Our studies,
and those from other laboratories, suggest that Beclin 1
coordinately regulates the autophagy and membrane traffick-
ing involved in several physiological and pathological
processes. This review focuses on the Beclin 1 network of
associating proteins and its regulation of several critical
Beclin 1 is a BH3-only domain autophagy protein
Beclin 1 is a novel Bcl-2-homology (BH)-3 domain only
protein.9The embryonic phenotype of Beclin 1 null mice is
even more severe than that of other autophagy gene-deficient
mice, which die in early embryonic development (E7.5 or
earlier) with defects in proamniotic canal closure.10Beclin 1
is expressed in many human and murine tissues, and
is localized primarily within cytoplasmic structures, including
the ER, mitochondria and the perinuclear membrane.
In human colon cancer tissue observed via immunohisto-
chemistry, Beclin 1 is distributed within the plasma-
membrane, the cytoplasm and the nucleus.11Beclin 1
contains three identified structural domains: a BH3 domain
(amino acids 114–123) at the N-terminus, a central coiled-coil
domain (CCD, amino acids 144–269) and an evolutionarily
conserved domain (ECD, amino acids 244–337) (Figure 2a).
The ECD is essential for Beclin 1’s ability to mediate
autophagy and to inhibit tumorigenesis. Beclin 1 also contains
a short leucine-rich amino acid sequence that is responsible
for its efficient nuclear export signal (NES) (Figure 2a).
Mutations of the Beclin 1 NES interfere with its abilities to
promote nutrient deprivation-induced autophagy and sup-
press tumorigenesis.12Anti-apoptotic Bcl-2 family members
interact with the BH3 domain of Beclin 1. The activating
molecule in Beclin 1-regulated autophagy (Ambra1)/UV
radiation resistance-associated gene (UVRAG)/Atg14L inter-
act with the CCD domain, and PI3KC3/Vps34 interacts with
the ECD and CCD domains.
As a BH3-only domain protein, Beclin 1 also has the
to serve as a platform enabling rapid nucleation of its
associating proteins. The CCD, a universal oligomerization
domain, mediates Beclin 1 self-interaction and dimer forma-
tion in vivo and in vitro.13,14The amino terminus binds
less effectively than the CCD to contribute to Beclin 1 self-
assembly.13More specifically, the Bcl-2-binding domain of
Beclin 1 is not essential for its self-interaction.13Early studies
suggested that Bcl-XL and UVRAG cause a monomer-dimer
switch in Beclin 1 (Noble et al.14). The viral Bcl-2 homologue
M11 partially disrupts the Beclin 1 homo-oligomer.15Interest-
ingly, viral Bcl-2 binds independently to two sites on the
Beclin 1 dimer, one with high affinity and one with lower
affinity, whereas human Bcl-XL binds to both sites equally
with relatively low affinity by sedimentation equilibrium and
velocity analysis.14Beclin 1 self-interaction is not affected
by amino acid deprivation, rapamycin-induced autophagy,
PI3KC3/Vps34, Bcl-XL or UVRAG overexpression in live
cells.13Therefore, regulation of Beclin 1 oligomerization
in vivo is more complex. We do not yet know whether
other Bcl-2 family proteins or cofactors influence Beclin 1
Transcriptional regulation of Beclin 1 in autophagy
Increasing evidence suggests that nuclear factor (NF)-kB,
E2F transcription factors (E2F) and microRNAs (miRNAs) are
involved in regulation of Beclin 1 expression in autophagy
p65, one of the canonical NF-kB pathway components,
and proteinlevels,leadingtoautophagyinT cells.16However,
the relationship between NF-kB and regulation of autophagy
seems puzzling and complex. NF-kB has emerged as a
negative regulator of autophagy, as induced by tumor
in some cell lines.17On the other hand, other studies suggest
NF-kB and its counter-regulator IKK have an activating role
in autophagy.18Constitutively, active IKK subunits stimulate
autophagy.18Remarkably, NF-kB p65 positively modulates
Beclin 1 transcription and autophagy.16Further study, likely
evaluating regulatable systems in various cellular targets
in vivo, will be required to sort out the complexity.
Recent work suggests that E2F1 binds Atg1/ULK1, LC3,
DRAM1, BNIP3, ULK2, Atg4, Atg7, GABARAPL2, Atg9A,
Atg10, Atg12, p73, Apaf1 and caspase promoters, increasing
their expression and regulating autophagy and apoptosis.19
A ChIP-on-chip study suggested that Beclin 1 could be an
E2F target.20Indeed, E2Fs can directly transactivate the
Beclin 1 promoter (Figure 2a).21When E2F-1 or -2 or -3 is
depleted, Beclin 1 mRNA and protein levels are significantly
reduced in the U2OS cell line.21
miRNAs are post-transcriptional regulators that bind to
complementary sequences in the three prime untranslated
regions (30UTRs) of target mRNAs, usually resulting in gene
silencing. The miR-30a-binding sequences in the 30-UTR of
Beclin 1 contributes to the modulation of Beclin 1 expression
by miR-30a (Figure 2a). Transfection with a miR-30a mimic
decreased Beclin 1 mRNA and protein expression; whereas
treatment with a miR-30a antagomir resulted in upregulation
of Beclin 1 (Zhu et al.22). It is not known whether miR-30a
directly mediated the activity of NF-kB and E2F during
Beclin 1 expression. Consistent treatment of tumor cells with
a miR-30a mimic results in decreased autophagic activity in
Modification of Beclin 1 by phosphorylation and
ubiquitination in autophagy
Beclin 1 is a new phosphorylation substrate of the death-
associated protein kinase (DAPK),23a tumor suppressor lost
functions of cell death and growth, DAPK can stimulate auto-
phagy and membrane blebbing by binding to LC3. Notably,
DAPK phosphorylatesBeclin 1 onThr119 attheBH3 domain,
Beclin 1 complexes
R Kang et al
Cell Death and Differentiation
thus promoting the dissociation of Beclin 1 from Bcl-2-like
proteins, which in turn induces autophagy.23The relationship
between Beclin 1 and other substrates of DAPK in autophagy
Phosphorylation of Bcl-2 by the c-Jun N-terminal kinase 1
(JNK1), located within the nonstructural loop of Bcl-2, is
another mechanism that reduces the interaction between
Beclin 1 and its inhibitor.24We find that high mobility group
box 1 (HMGB1) promotes the phosphorylation of Bcl-2 by
extracellular signal-regulated kinase (ERK), the subsequent
dissociation of Beclin 1 from Bcl-2, and the induction of
autophagy.25Thus, the interaction between Beclin 1 and its
inhibitors is dynamic and subject to regulation by phosphory-
lation of either one of the two partners in this complex.
Unfortunately, we know almost nothing about how these
mitogen-activated protein kinases (MAPKs, e.g., JNK1 and
ERK) might induce conformational changes between Beclin 1
and its binding partners, preventing their interaction with
one another. Autophagy is negatively regulated by the mTOR
and Ras-cAMP-PKA pathways. Interestingly, LC3 is a direct
substrate of PKA, and its phosphorylation prevents recruit-
ment of LC3 to autophagosomes (Figure 2b).26Thus, DAPK
and PKA target individual substrates, such as Beclin 1 and
LC3 in autophagy.
The tumor necrosis factor receptor-associated factor 6
(TRAF6) and the deubiquitinating enzyme A20 control
K63-linked ubiquitination of Beclin 1 to trigger autophagy.27
The K63-linked ubiquitination of Beclin 1 facilitates oligo-
trigger the formation of autophagosomes. It is important
that future studies assess the state of phosphorylation and
ubiquitination of Beclin 1 in the setting of autophagy.
Complex I Complex II
Conversely, miR-9 increases autophagy by regulating histone deacetylases activity in lymphoma cells (not shown). Structurally, Beclin 1 has a BH3 domain, a central
CCD and an ECD. (b) Phosphorylation and ubiquitination modification regulates autophagy. (c) In yeast, Atg6-Vps34-Vps15 complexes I and II regulate autophagy
and Vps, respectively. (d) In mammals, Beclin 1-Vps34-Vps15 core complexes and Beclin 1’s binding proteins. (e) Models of Beclin 1–Bcl-2 complex dissociation
in autophagy. (f) Model of the role of the three Beclin 1-Vps34-Vps15 complexes. The Atg14L complex functions positively in autophagosome formation. The UVRAG
complex functions positively in autophagosome and endosome maturation. The Rubicon complex functions negatively in autophagosome and endosome maturation
(figure modified from49,74)
The complex Beclin 1 network. (a) NF-kB and E2F positively regulates Beclin 1 expression, whereas miR30a negatively regulates Beclin 1 expression.
Beclin 1 complexes
R Kang et al
Cell Death and Differentiation
Induction of autophagy by Beclin 1-Vps34-Vps15 core
Although more and more Beclin 1-binding proteins and
complexes are being identified in mammals, each of the
individual complexes seems to recycle various elements
derived from other cellular processes. Beclin 1 (Atg6/Vps30),
PI3KC3/Vps34 and Vps15 (Figure 2d) have been predicted to
regulate autophagy in a similar manner to yeast (Figure 2c).
The phosphoinositol-3-kinase (PI3K) family is divided into
three different classes in mammals – class I, class II and
class III. Yeast cells have only a solitary class III PI3K and
Vps34. Vps34 forms at least two distinct PI3K complexes in
Vps30 and Atg14, and complex II containing Vps34, Vps15,
Atg6/Vps30 and Vps38 (Itakura et al.28). Complexes I and II
function in autophagy and the Vps pathway, respectively.
Complex II is more abundant than complex I, suggesting that
Atg6/Vps30-Vps34-Vps15 is primarily involved in the Vps
pathways under normal conditions and that yeast autophagy
is strictly regulated at a basal level in yeast. Interestingly,
recent studies show that Vps34 is phosphorylated on Thr159
by cyclin-dependent kinase 1 (Cdk1), which negatively
regulates its interaction with Beclin 1 during mitosis in
mammalian cells (Figure 2b).29Vps34 also appears to have
a role in other membrane-trafficking processes distinct from
autophagy. It would be interesting to know if Vps34
phosphorylation affects these processes, and if cell cycle
proteins are required for autophagy.
Inhibition of autophagy by Beclin 1–Bcl-2 /Bcl-XL
BH3 receptor domain within Bcl-2 or Bcl-XL, disrupted the
Beclin 1–Bcl-2 complex, resulting in the stimulation of
autophagy. The relationship between Beclin 1 and Bcl-2/
Bcl-XL is complicated. Beclin 1 cannot neutralize the anti-
apoptotic function of Bcl-2, which is exerted at the mito-
chondrial membrane.30In contrast, Bcl-2 or Bcl-XL reduces
the pro-autophagic activity of Beclin 1 (Pattingre et al.31;
Maiuri et al.32). Interestingly, ER-localized Bcl-2, but not
mitochondrial-localized Bcl-2, inhibits autophagy,31which is
consistent with the older notion that ER-associated class III
PI3K activity may be crucial in the nucleation of autophago-
some formation. Beclin 1 can colocalize with Bcl-XL within
mitochondria via its BH3 domain,14suggesting a differential
role of Bcl-XL in Beclin 1 complex when compared with Bcl-2.
Currently, there are several different means to regulate
dissociation of Beclin 1 and Bcl-2/Bcl-XL during autophagy in
mammalian cells (Figure 2e). These include: (1) competitive
proteins. The interaction between Beclin 1 and the anti-
apoptotic proteins is inhibited by tBid, Bad and BNIP3, but not
by Bax and Bak.33Moreover, the pro-apoptotic BH3-only
proteins such as BNIP3, Bad, Noxa, Puma, BimEL and Bik all
induce autophagy.33(2) JNK1 or ERK-mediated phosphory-
lation of Bcl-2 (Wei et al.24; Tang et al.25) or DAPK-mediated
phosphorylation of Beclin 1 (Zalckvar et al.23). Phosphory-
lation of DAPK at Ser 735 by ERK increases the catalytic
activity of DAPK both in vitro and in vivo.34In contrast, DAPK
promotes the cytoplasmic retention of ERK, thereby inhibiting
ERK signaling in the nucleus.34Furthermore, DAPK regulates
JNK signaling by binding and activating protein kinase D
under conditions of oxidative stress.35Future studies are
required to define the crosstalk between the MAP kinases
(e.g., JNK, ERK) and DAPK to regulate phosphorylation/
dephosphorylation events in autophagy. (3) Competitive
displacement of Bcl-2 by other Beclin 1-binding proteins such
as HMGB1, UVRAG or Atg14L/Barkor; this likely initiates a
program of heightened anti-apoptotic state, promotes auto-
phagy, and ultimately protects the cell during cell stress.
(4) NAF-1 (nutrient-deprivation autophagy factor-1) dysfunc-
tion. NAF-1 is a component of the inositol-1,4,5 trisphosphate
(IP3) receptor complex, which contributes to Beclin 1–Bcl-2
interaction within the ER. NAF-1 binds Bcl-2 and this inter-
part on its redox sensitive CDGSH iron/ sulphur-binding
domain.36ROS are important signaling molecules that initiate
autophagy. Beclin 1 is also a cysteine-rich protein. Whether
redox regulates the structure and function of Beclin 1 is
unknown. (5) Beclin 1 self-interaction: Beclin 1 can form large
homo-oligomers, which may provide a platform for further
protein–protein interactions and displacement of Bcl-2 or
Bcl-XL. In general, the anti-autophagic binding of Bcl-2
promotes Beclin 1 homodimerization, and this prevents
heterodimerization with Atg14L or UVRAG. It is not clear
whether the disulfide bond is involved in the formation of
Beclin 1 homo-oligomers. (6) TRAF6-mediated ubiquitination
of Beclin 1. The deubiquitinating enzyme A20 reduces
ubiquitination of Beclin 1 and limits the induction of autophagy
in response to Toll-like receptor (TLR) signaling, increasing
the interaction of Bcl-2 with Beclin 1 (Shi and Kehrl27).
Other Beclin 1-binding proteins in autophagy
Atg14L/Barkor. Atg14L, also known as Barkor,37contains
two CCD that are required for binding the CCD regions
of Beclin 1 and Vps34. Atg14L shares an 18% sequence
identity and a 32% sequence similarity with yeast Atg14. In
yeast, Atg14 acts as an adaptor molecule promoting
interaction of Vps30 and the rest of the complex. It is
responsible for targeting the entire complex to the PAS
(Figure 2c). Similar to the role of Atg14 in yeast, human
Atg14L is required for autophagosome formation.38
mammals, Atg14L localizes to the ER.39Furthermore,
Atg14L colocalizes with Atg5 and Atg16L1 on the isolation
membranes during autophagy.28
UVRAG form two distinct complexes with Beclin 1-Vps34 in
autophagy (Figure 2f). The interaction between Beclin 1 and
Vps34 is not affected by Atg14L. In contrast, Beclin 1 is
required for the interaction between Vps34 and Atg14L.37
Loss of Beclin 1 or Vps34 greatly reduces Atg14L protein
levels, suggesting that these proteins have some non-
autophagic functions or altered stability in the absence of
forming a complex with Beclin 1/Vps34. Interestingly, PI3K
activity is required for starvation-induced Atg5 and ATG16L
punctae formation, but not for Atg14L punctae, suggesting
that precursor structures of Atg14L form independent of
Vps34 and Beclin 1 (Itakura et al.28).
Notably, Atg14L and
Beclin 1 complexes
R Kang et al
Cell Death and Differentiation
cancer cells through autophagy-dependent40or -independent
mechanisms.41Remarkably, UVRAG promotes autophago-
some formation by activation of the Beclin 1 complex40and
autophagosome maturation by recruitment of the fusion
machinery to the late endosome in mammalian cells42
(Figure 2f). Suppressing UVRAG expression in cells does
not affect autophagic flux or autophagosome formation.28,41
UVRAG promoted autophagosome maturation, and endocytic
trafficking is independent of Beclin 1. These findings suggest
that UVRAG has some unknown role(s) in regulating
autophagy dynamics and membrane trafficking.
UVRAG directly binds Beclin 1 through the CCD.40UVRAG
can disrupt the Beclin 1-dimer interface, forming a hetero-
dimer with Beclin 1 (Noble et al.14). However, other study
shows that overexpression of UVRAG has no effect on
Beclin 1 self-interaction.13Loss of Beclin 1 or Vps34 reduces
UVRAG protein levels in starvation-induced autophagy.28
However, UVRAG and Atg5/Atg16L1 do not colocalize during
heightened autophagy. Moreover, endogenous UVRAG
punctae were also not colocalized with LC3 under starvation
conditions, suggesting that UVRAG punctae do not represent
autophagy-related structures. Indeed, UVRAG primarily
resides in endocytic compartments such as Rab9-positive
late endosomes, as well as partially with Rab5 and Rab7
(Itakura et al.28; Liang et al.42), raising the possibility that it
has an additional non-autophagic role.
Bif-1. Endophilin B1/Bax-interacting factor 1 (Bif-1) is
localized in the cytosol and regulates the membrane
dynamics of organelles, such as the Golgi complex and
mitochondria, as well as autophagosomes. In autophagy,
Bif-1 interacts with Beclin 1 through UVRAG and functions
as a positive mediator of PI3KC3 and the induction of
autophagy in mammalian cells.43Loss of Bif-1 significantly
suppresses PI3KC3 activation and the formation of auto-
phagosomes. As in Beclin 1- and UVRAG-deficient mice,
knockout of Bif-1 promotes spontaneous tumorigenesis in
mice, although embryonic Bif-1?/?mice develop normally.43
Bif-1 accumulates in punctate structures, along with Atg5 and
LC3, suggesting that Bif-1 is involved in the early stages
of autophagosome formation and may have a role in the
biogenesis and/or expansion of phagophores. Moreover,
Bif-1 interacts with Beclin 1 through UVRAG (Figure 2f).
Rubicon. RUN domain protein as Beclin 1 interacting and
cysteine-rich containing (Rubicon) was recently identified
as another novel Beclin 1-binding partner.38,44Rubicon
contains a RUN domain, an asparagine-rich region, a CCD,
and a cysteine-rich region.38,44Rubicon localizes to the
late endosome/lysosome, but not the autophagosome. In
contrast to Atg14L, Rubicon negatively regulates autophagy,
likely throughinhibition of autophagosome
(Figure 2f). Overexpression of Rubicon remarkably reduces
PI3KC3/Vps34 activity and impairs the acidification of LC3-
associated vacuoles. Knockdown of Rubicon by shRNA
leads to a dramatic increase in LC3 punctae formation, even
under nutrient-rich conditions in mammalian cells. Over-
expression of Rubicon also results in the formation of many
abnormal structures that are positive for the late endosome/
lysosome marker lysosomal-associated membrane protein 1
(LAMP-1) and the multivesicular body marker lysobisphos-
phatidic acid. However, Beclin 1 does not appear to be
involved in the formation of aberrant endosomal structures
resulting from Rubicon overexpression that apparently inhibit
autophagosome maturation. At present, Beclin 1’s partici-
pation in Rubicon-mediated endocytic trafficking is unclear.
In addition, careful analysis of the previous study38Beth
Levine’s group unpublished data have confirmed that
Rubicon likely also inhibits autophagosome initiation.
Ambra1. Ambra1 has a role in the development of the
nervous system.45Ambra1 functional deficiency in mouse
embryos leads to severe neural tube defects associated
with autophagy impairment, accumulation of ubiquitinated
proteins, unbalanced cell proliferation, and excessive apop-
totic cell death. As a Beclin 1-binding protein (Figure 2d),
downregulation of Ambra1 results in a remarkable decrease
in rapamycin and nutrient deprivation-induced autophagy,
whereas Ambra1 overexpression increases basal and
rapamycin-induced autophagy. In addition, recent studies
demonstrate that DLC1, a component of the microtubule-
based molecular dynein motor complex, is a negative
regulator of Ambra1 by yeast two-hybrid assays.46Ambra1
is required for Beclin 1 translocation to the ER following
induction of autophagy.46These findings provide an under-
standing at the molecular level detailing the relationship
HMGB1. HMGB1 is a chromatin-associated nuclear protein
and extracellular damage-associated molecular pattern
molecule.47,48Recently, we have shown that HMGB1 is a
novel Beclin 1-binding protein important in sustaining
autophagy.25,49Deletion, depletion or inhibition of HMGB1
in mouse embryonic fibroblasts or tumor cells markedly
diminishes autophagy. Endogenous HMGB1 interacts with
Beclin 1 in normal and tumor cells.49Structurally, HMGB1 is
composed of three domains: two positively charged domains
(A box and B box) and a negatively charged carboxyl
terminus (the acidic tail). The three cysteines of human
HMGB1 are encoded at positions 23, 45 (A box) and 106
(B box). C106S mutants have much higher cytosolic levels
of HMGB1 and demonstrate enhanced binding to Beclin 1,
leading to the subsequent dissociation of Bcl-2 from Beclin 1
in mammalian cells. Meanwhile, C23S and C45S mutants
lose their ability to mediate autophagy as they are unable to
bind Beclin 1 and therefore cannot disrupt Bcl-2–Beclin 1
interactions (Figures 2d and e). These findings demonstrate
that oxidation of HMGB1 regulates its localization and ability
to sustain autophagy. Moreover, cytosolic translocation of
HMGB1 is necessary, but may not be sufficient, to enhance
In addition, HMGB1 is released with sustained autophagy,
late apoptosis and necrosis in mammalian cells.50–53Delivery
of exogenous HMGB1 protein to cells triggers autophagy or
apoptosis in cancer cells, depending on its redox status and
receptors. Reducible HMGB1 (i.e., where the cysteines are
not terminally oxidized) binds to the receptor for advanced
glycation end products (RAGE), induces Beclin 1-dependent
Beclin 1 complexes
R Kang et al
Cell Death and Differentiation
autophagy, and promotes pancreatic or colon tumor cell line
resistance to chemotherapeutic agents and ionizing radiation.
Moreover, RAGE sustains autophagy and limits apoptosis,
In contrast, oxidized HMGB1 increases the cytotoxicity of
these agents and induces apoptosis via the mitochondrial
pathway. We propose a new function for HMGB1 within the
tumor microenvironment: as a regulator of cell death and
survival, suggesting that HMGB1 has an important functional
role in cross-regulating apoptosis and autophagy.
nPIST. Neuronal isoform of protein-interaction, specifically
with TC10 (nPIST), was originally discovered as glutamate
receptor d2 (GluRd2) and a Beclin 1-binding protein by yeast
two-hybrid studies.56nPIST can regulate the ability of
Beclin 1 to induce autophagy.56nPIST binds GluRd2 by a
PDZ domain, whereas nPIST binds Beclin 1 by a CCD
(Figure 2d). These interactions provide a physical linkage
between the GluRd2 receptor and Beclin 1.
VMP1. The pancreatitis-associated protein, vacuole mem-
brane protein 1 (VMP1) is an ER transmembrane protein and
candidate marker of autophagosomal membranes with no
known homologues in yeast (Figure 2d). VMP1 is induced by
starvation and rapamycin treatment, and its overexpression
triggers conversion of LC3-I to LC3-II and autophago-
some formation in mammalian cells.57,58Moreover, VMP1
hydrophilic C-terminal region (Atg domain) has proved to be
essential for Beclin 1 interaction and autophagy induction. Atg
mutant VMP1 expression fails to induce LC3 recruitment, and
the triple colocalization as well as interaction of VMP1 and
Beclin 1 is abolished. Interestingly, tumor protein 53-induced
nuclear protein 2 (TP53INP2) can translocate from the nucleus
to the autophagosome structures and interact with LC3 and
VMP1, following activation of autophagy by rapamycin or
starvation.59It is unknown, however, whether Beclin 1
mediates interaction between TP53INP2 and LC3/VMP1.
(SLAMF1; CD150), a microbial/measles virus sensor, is a
novel Beclin 1-binding protein involved in immune cell killing
of Gram-negative bacteria through the phagosome and
autophagy (Figure 2d).60Loss of SLAM in macrophages
decreased the activity of the cell membrane nicotinamide
adenine dinucleotide phosphate oxidase NOX2 complex, one
of the key mechanisms by which phagocytes kill bacteria.60
IP3R. IP3R is a membrane glycoprotein complex acting as
Ca2þchannel, activated by IP3. In addition to apoptosis,
the IP3R also regulates autophagy. IP3R antagonists or
knockdown of IP3R by RNAi induces autophagy.61In
contrast, IP3R agonists inhibit autophagy. Notably, IP3R
antagonists induce autophagy by disrupting a molecular
complex formed by interaction of IP3R and Beclin 1
(Figure 2d), which is increased or inhibited by overexpres-
sion or knockdown of Bcl-2.61In cells, IP3R-mediated Ca2þ
fluxes are irrelevant to the regulation of autophagy.
Knockdown of IP3R impairs the activity of mTORC1 but
not the Beclin 1 core complex in chicken DT40 B-lymphocyte
PINK1. PTEN-induced putative kinase 1 (PINK1) is a serine/
threonine protein kinase that localizes to mitochondria. It has
been implicated in protecting cells from stress-induced
mitochondrial dysfunction by regulation of mitophagy.63
Moreover, the full-length PINK1, but not its cleaved iso-
forms, or a mutant protein truncated at the C-terminus,
interacts with the pro-autophagic protein Beclin 1 and
enhances autophagy (Figure 2d).64
Survivin. Survivin is an anti-apoptotic protein highly expres-
sed during fetal development and malignancy. Recent study
indicates that interaction of Beclin 1 with survivin regulates
sensitivity of human glioma cells to TRAIL (a death receptor
ligand) – induced apoptosis (Figure 2d).65This study
presents a possible mechanism regulating the cross-talk
between apoptosis and autophagy by Beclin 1-mediated
degradation of survivin.
Pathogen-derived Beclin 1 interaction partners. In recent
years, a number of pathogen-derived proteins that also
bind to Beclin 1 have been characterized. These include
vBcl-2 (KSHV and murine gHV68 M11), ICP34.5 (HSV),
M2 (influenza) and Nef (HIV). vBcl-2 of g-herpesviruses
including KSHV and M11 can inhibit autophagy via a direct
interaction with Beclin 1 (Pattingre et al.31). The M11 has
higher affinity to Beclin 1 when compared with other vBcl-2
(Ku et al.15; Sinha et al.66). The herpes simplex virus protein
ICP34.5 interacts with Beclin 1 to block double-stranded
RNA-activated protein kinase R-dependent macroautophagy
induction, which limits neurovirulence by HSV-1 (Orvedahl
et al.67). Recent studies also provide evidence that HIV-1 Nef
and the influenza M2 proteins interact with Beclin 1 and block
that Beclin 1 complexes not only promote autophagosome
formation but also maturation in different pathogens, which
regulates host response in immunologic defense.
These studies suggest
Crosstalk between apoptosis and autophagy by Beclin 1
In general, the ‘BH3-only members’ of Bcl-2 family can bind to
and antagonize the pro-survival proteins leading to increased
apoptosis. However, unlike other known BH3-only proteins,
Beclin 1 does not function asa pro-apoptotic molecule, even if
it is overexpressed. Bcl-2, as it interacts with Beclin 1, does
not lose its anti-apoptotic potential.30In contrast, Beclin 1 has
an anti-apoptotic role in several settings including TRAIL,
chemotherapy, irradiation, immunotherapy, nutrient depriva-
tion, angiogenesis inhibitors and hypoxia. In C. elegans,
depletion of Beclin 1 triggers CED-3/caspase-dependent
programmed cell death. Bid knockdown protects cancer cells
against apoptosis and induces autophagy, manifest by
increased expression of Beclin 1. The precise mechanism
related to unregulated autophagy as an adaptive or anti-injury
mechanism, clearing apoptotic cells.
Caspases are cysteine aspartyl proteases that have a
cardinal role in apoptotic cell death. Interestingly, caspases
can cleave Beclin 1 in apoptosis, thereby destroying its
pro-autophagic activity.70,71For example, caspase-3-, 7- and
8-mediated cleavage of Beclin 1 generates N- and C-terminal
Beclin 1 complexes
R Kang et al
Cell Death and Differentiation
The C-terminal fragments translocate to mitochondria and
sensitize cells to apoptotic signals.70This process represents
an amplifying loop for inducing massive apoptotic cell death.
Apoptosis induced by the proapoptotic protein Bax reduced
autophagy by enhancing caspase-mediated cleavage of
Beclin 1 at D149 (Luo and Rubinsztein71). Non-cleavable
Beclin 1 as well as Bcl-XL restores Bax-reduced autophagy.71
Moreover, TRAIL, a death receptor ligand, triggers the
caspase-mediated cleavage of Beclin 1 in HeLa cells. How-
ever, recent studies indicate that active caspase-8, a death
that a feedback mechanism that cross-regulates autophagy
and apoptosis exists. Indeed, autophagy and apoptosis share
common stimuli and signaling pathways; therefore cell life or
death, depends on the cell response and which process is
dominant. Although apoptosis-associated cleavage of Beclin 1
and Atg5 inactivates autophagy, the cleavage of Atg4D by
caspase-3 generates a fragment with increased autophagic
activity. Further investigation of these cleavage events will be
importantforgaininggreater knowledge oftheinterrelationship
between autophagy and apoptosis.
Through the analysis of Beclin 1 and its guests at the table of
self-eating, great advances have been made in our under-
standing of the mechanism and roles of autophagy in cell
homeostasis. Intriguingly, Beclin 1 can intervene at every
major step in autophagic pathways, from autophagosome
formation, to autophagosome/endosome maturation. Many of
these effects are mediated through the activation of specific
Beclin 1-binding proteins, including autophagic inducers and
autophagic inhibitors. However, the assembly of the Beclin 1
complexes appears in a cell- or tissue-dependent fashion.
One possible explanation is that their interaction with Beclin 1
may be relatively unstable, transient or occur only under
specific conditions. Beclin 1 likely has additional functions
other than autophagy. Further studies will reveal the precise
role of each of the identified Beclin 1 complexes in autophagy
and specific disease contexts, and determine whether
stimulation or inhibition of autophagy is more beneficial.
Another important task in the coming years will be matching
differences between autophagic and apoptotic variants with
the individual conditions that result in tumor development.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements. We thank the numerous colleagues in the field of
autophagy, who through their animated discussions have helped shape this review.
We would particularly like to thank Dr. Beth Levine who generously critiqued the
article and improved it based on her insights and pioneering work in the area
of Beclin 1 biology. We also thank Christine Heiner for careful editing of the paper.
The development of a metabolism and mitochondria in disease working group with
Dr. Bennett Van Houten, who has provided reflection and encouragement for our
studies is appreciated. Work in our laboratory is generously supported by the
inhibition. During sustained exposure to apoptotic stimuli, caspase-mediated cleavage of Beclin 1 generates fragments (‘N’ and ‘C’) that lose their ability to induce autophagy.
The C-terminal fragment translocates to the mitochondria and sensitizes cells to apoptotic signals. Although apoptosis-associated cleavage of Beclin 1 and Atg5 inactivates
autophagy, the cleavage of Atg4D by caspase-3 generates a fragment with increased autophagy activity. Moreover, autophagy inhibits apoptosis partly by degrading active
caspase-8 or preventing activation of Bid by Beclin 1
Crosstalk between apoptosis and autophagy. Autophagy and apoptosis share common stimuli and signaling pathways, and exhibit some degree of mutual
Beclin 1 complexes
R Kang et al
Cell Death and Differentiation
University of Pittsburgh Department of Surgery (Dr. Timothy Billiar), the University
of Pittsburgh Cancer Institute (Dr. Nancy Davidson) and the National Institutes
of Health via a grant from the National Cancer Institute (P01 CA 101944-04 to
Michael T Lotze, MD).
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