Autophagy

Autophagy

Published by Taylor & Francis

Online ISSN: 1554-8635

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Figure 3. Types of regulated cell death. Regulated cell death is a biologically controlled process involved in various physiological or pathological events. It can be divided into apoptotic and non-apoptotic cell death. Compared with apoptosis, which generally requires the activation of caspase proteases, nonapoptotic cells are mostly caspase-independent and have the morphological characteristics of necrosis.
Figure 4. Role of copper in apoptosis. (A) Mechanism of copper-induced apoptosis. Copper induces apoptosis primarily through the induction of ROS, DNA damage, and proteasome inhibition. The apoptotic process is initiated by mitochondria-intrinsic apoptotic signals. CYCS-activated CASP9 propagates the apoptotic cascade by activating downstream CASP3, a key apoptosis execution protein that participates in the cleavage of multiple substrates. Furthermore, AIFM1 is released from mitochondria and induces caspase-independent apoptosis by attacking DNA. (B) the role of TP53 in copper-induced apoptosis. Copper induces TP53-dependent apoptosis by activating transcription of TP53 target genes, including BAX, CDKN1A/p21, PMAIP1/NOXA, and BBC3/PUMA. Copper also induces TP53-independent apoptosis by inhibiting ribosome synthesis and inducing nucleolar stress. (C, D) the anti-apoptosis role of copper. IL17 released by immune cells can increase STEAP4-mediated intracellular copper levels, leading to 5-fluorouracil (5-FU) resistance by activating the anti-apoptotic XIAP protein. Copper triggers the upregulation of CD274/PD-L1, which induces tumor immune escape by binding with PDCD1/PD-1 on activated T cells.
Figure 5. Role of copper in paraptosis. Paraptosis is a form of regulated necrosis characterized by vacuolation of mitochondria or ER. Copper promotes paraptosis by inducing proteasome inhibition, ER stress, Ca 2+ imblance, and ROS production.
Figure 6. Role of copper in pyroptosis. Copper promotes pyroptosis by inducing ROS production and ER stress, which leads to the formation of the NLRP3 inflammasome and the creation of membrane pores through the action of GSDMD.
Figure 7. Role of copper in ferroptosis. (A) Pro-ferroptotic role of copper. Copper increases intracellular ROS through Fenton-like reactions or mitochondrial damage. Subsequently, increased ROS lead to lipid peroxidation of the plasma membrane or membrane structures. Furthermore, copper directly binds to GPX4 and induces GPX4 oligomerization, ultimately promoting the autophagic degradation of GPX4 mediated by the autophagy receptor TAXIBP1. (B) Anti-ferroptotic role of copper. COMMD10 is a key copper metabolism protein that reduces intracellular copper levels. Copper promotes HIF1A stabilization, thereby increasing transcription of HIF1A target genes, including FABP3, FABP7, CP, and SLC7A11. Copper-mediated upregulation of these HIF1A target genes suppresses lipid peroxidation and ferroptosis.

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Copper metabolism in cell death and autophagy

April 2023

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492 Reads

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246 Citations

Qian Xue

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Rui Kang

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Daniel J Klionsky

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[...]

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Xin Chen
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Aims and scope


Autophagy publishes research on autophagic processes, to advance understanding of the connection between autophagy and human health and disease.

  • Autophagy publishes peer-reviewed research on all aspects of autophagic processes.
  • The aim of Autophagy is to be the premiere journal publishing high quality papers in the field which has advanced tremendously, due in large part to the multiple connections between autophagy and various aspects of human health and disease.
  • Autophagy covers the following topics: autophagic processes (i.e. the lysosome/vacuole dependent degradation of intracellular material); the connections between autophagy and various aspects of human health and disease including, cancer, neurodegeneration, aging, diabetes, myopathies and heart disease; and we are interested in all experimental systems, from yeast to human. Suggestions for appropriate specialized topics are welcome…

For a full list of the subject areas this journal covers, please visit the journal website.

Recent articles


SESN1 negatively regulates STING1 to maintain innate immune homeostasis
  • Article

February 2025

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2 Reads

Lingxiao Xu

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Hongqian Zhang

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Zuocheng Qiu

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[...]

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Mingyu Pan











Chaperone-mediated autophagy contributes to chromosomal stability by controlling TTC28 degradation

February 2025

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2 Reads

While macroautophagy (autophagy) contributes to maintaining chromosomal stability via multiple pathways, including regulating chromatin ubiquitination and cytoplasmic DNA fragment degradation, the impacts of microautophagy and chaperone-mediated autophagy (CMA) on maintaining chromosomal stability are not known. The TTC28 (tetratricopeptide repeat domain 28) gene is frequently mutated and downregulated in human cancers. The molecular mass of the TTC28 protein is 271 kDa, which makes its functional study very difficult. Recently, we reported that TTC28 plays a key role in maintaining chromosomal stability, probably through regulating mitosis and cytokinesis, and that TTC28 downregulation may contribute to the high chromosomal instability (CIN) of cancer cells, according to the results of serial experiments and bioinformatics analyses. Notably, our findings demonstrate that TTC28 is a substrate of CMA and that the CMA pathway also plays a role in maintaining chromosomal stability in a TTC28-dependent manner. These findings demonstrate that CMA-mediated degradation is a master regulator of the ability of TTC28 to maintain genome stability.









PLK2 disrupts autophagic flux to promote SNCA/α-synuclein pathology

January 2025

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6 Reads

The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology of Parkinson disease (PD). PLK2 (polo like kinase 2) is an evolutionarily conserved serine/threonine kinase that is more abundant in the brains of all family members, is highly expressed in PD, and is linked to SNCA deposition. However, in addition to its role in phosphorylating SNCA, the role of PLK2 in PD and the mechanisms involved in triggering neurodegeneration remain unclear. Here, we found that PLK2 regulated SNCA pathology independently of S129. Overexpression of PLK2 promoted SNCA preformed fibril (PFF)-induced aggregation of wild-type SNCA and mutant SNCAS129A. Genetic or pharmacological inhibition of PLK2 attenuated SNCA deposition and neurotoxicity. Mechanistically, PLK2 exacerbated the propagation of SNCA pathology by impeding the clearance of SNCA aggregates by blocking macroautophagic/autophagic flux. We further showed that PLK2 phosphorylated S1098 of DCTN1 (dynactin 1), a protein that controls the movement of organelles, leading to impaired autophagosome-lysosome fusion. Furthermore, genetic suppression of PLK2 alleviated SNCA aggregation and motor dysfunction in vivo. Our findings suggest that PLK2 negatively regulates autophagy, promoting SNCA pathology, suggesting a role for PLK2 in PD.Abbreviation: AD: Alzheimer disease; AMPK: AMP-activated protein kinase; CASP3: caspase 3; DCTN1: dynactin 1; LBs: lewy bodies; LDH: lactate dehydrogenase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP2: microtubule associated protein 2; MTOR: mechanistic target of rapamycin kinase; NH4Cl: ammonium chloride; p-SNCA: phosphorylation of SNCA at S129; PD: Parkinson disease; PFF: preformed fibril; PI: propidium iodide; PLK2: polo like kinase 2; PRKAA/AMPK: protein kinase AMP-activated catalytic subunit alpha; shRNA: short hairpin RNA; SNCA: synuclein, alpha; SQSTM1/p62: sequestosome 1; TH: tyrosine hydroxylase; TX: Triton X-100; ULK1: unc-51 like autophagy activating kinase 1.


Nonreceptor tyrosine kinase ABL1 regulates lysosomal acidification by phosphorylating the ATP6V1B2 subunit of the vacuolar-type H+-ATPase

January 2025

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11 Reads

The vacuolar-type H+-ATPase (V-ATPase) is a proton pump responsible for controlling the intracellular and extracellular pH of cells. Its activity and assembly are tightly controlled by multiple pathways, of which phosphorylation-mediated regulation is poorly understood. In this report, we show that in response to starvation stimuli, the nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2, a subunit of the V1 domain of the V-ATPase, and phosphorylates ATP6V1B2 at Y68. Y68 phosphorylation in ATP6V1B2 facilitates the recruitment of the ATP6V1D subunit into the V1 subcomplex of V-ATPase, therefore potentiating the assembly of the V1 subcomplex with the membrane-embedded V0 subcomplex to form the integrated functional V-ATPase. ABL1 inhibition or depletion impairs V-ATPase assembly and lysosomal acidification, resulting in an increased lysosomal pH, a decreased lysosomal hydrolase activity, and consequently, the suppressed degradation of lumenal cargo during macroautophagy/autophagy. Consistently, the efficient removal of damaged mitochondrial residues during mitophagy is also impeded by ABL1 deficiency. Our findings suggest that ABL1 is a crucial autophagy regulator that maintains the adequate lysosomal acidification required for both physiological conditions and stress responses.Abbreviation: ANOVA: analysis of variance; Baf A1: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CRK: CRK proto-oncogene, adaptor protein; CTSD: cathepsin D; DMSO: dimethylsulfoxide; EBSS: Earle's balanced salt solution; FITC: fluorescein isothiocyanate; GFP: green fluorescent protein; GST: glutathione S-transferase; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PD: Parkinson disease; PLA: proximity ligation assay; RFP: red fluorescent protein; WT: wild-type.


Figure 2. Cargo hitchhiking pathways. (A) Degradation of the transcriptional regulator Ssn2/Med13. In normal physiological conditions, the CKM predominantly negatively regulates stress response genes, including ATG8. Following nitrogen stress (−N), the CKM is dissolved, mediated in part by the UPS-mediated destruction of Ssn8/cyclin C. Ssn2/Med13 translocates to the cytoplasm, interacting with Gle1, a conserved nuclear pore protein. Cytoplasmic Ssn2/Med13 interacts with the decapping protein Edc3, promoting its assembly into foci that localize to P-bodies (PB). Ssn2/Med13 utilizes Ksp1 as an autophagic receptor. Both Ksp1 and Ssn2/ Med13 are required for the autophagic degradation of Edc3, but only Ssn2/Med13 interacts directly with Ksp1. Snx4-Atg20 assists in Edc3 and Ssn2/Med13 degradation but is not drawn for clarity. (B) Cargo hitchhiking degradation of ribosomes in yeast. Following nitrogen starvation (−N), the 40S and 60S ribosomes are destroyed by various autophagic pathways. All pathways require Atg17, suggesting that they utilize phagophores built for the degradation of random cargo by bulk autophagy. Hab1 is the cargo hitchhiking receptor that recognizes a subset of 40S and 60S ribosomal proteins. The putative selective autophagy receptor (?) that recognizes the 60S ribosomal subunit remains unknown, but Bre5-Ubp3 deubiquitinases are required to degrade this conserved organelle. (C) Cargo hitchhiking degradation of glycogen (glycophagy) in yeast. Following nitrogen starvation (−N), glycogen is synthesized from UDP-glucose. Initially, glycogen is not recognized as an autophagic target. It is only after extended starvation that the cargo hitchhiking receptor Atg45 delivers it to 17C-built phagophores for eventual vacuolar proteolysis. Abbreviations: 17C: trimeric Atg17 scaffold complex; CKM: Cdk8 kinase module; NPC: nuclear pore complex; UPS: ubiquitin-proteasome system UDP: uridine diphosphate.
Cargo hitchhiking autophagy - a hybrid autophagy pathway utilized in yeast
  • Literature Review
  • Full-text available

January 2025

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10 Reads

Macroautophagy is a catabolic process that maintains cellular homeostasis by recycling intracellular material through the use of double-membrane vesicles called autophagosomes. In turn, autophagosomes fuse with vacuoles (in yeast and plants) or lysosomes (in metazoans), where resident hydrolases degrade the cargo. Given the conservation of autophagy, Saccharomyces cerevisiae is a valuable model organism for deciphering molecular details that define macroautophagy pathways. In yeast, macroautophagic pathways fall into two subclasses: selective and nonselective (bulk) autophagy. Bulk autophagy is predominantly upregulated following TORC1 inhibition, triggered by nutrient stress, and degrades superfluous random cytosolic proteins and organelles. In contrast, selective autophagy pathways maintain cellular homeostasis when TORC1 is active by degrading damaged organelles and dysfunctional proteins. Here, selective autophagy receptors mediate cargo delivery to the vacuole. Now, two groups have discovered a new hybrid autophagy mechanism, coined cargo hitchhiking autophagy (CHA), that uses autophagic receptor proteins to deliver selected cargo to phagophores built in response to nutrient stress for the random destruction of cytosolic contents. In CHA, various autophagic receptors link their cargos to lipidated Atg8, located on growing phagophores. In addition, the sorting nexin heterodimer Snx4-Atg20 assists in the degradation of cargo during CHA, possibly by aiding the delivery of cytoplasmic cargos to phagophores and/or by delaying the closure of expanding phagophores. This review will outline this new mechanism, also known as Snx4-assisted autophagy, that degrades an assortment of cargos in yeast, including transcription factors, glycogen, and a subset of ribosomal proteins.


Figure 4. PLpro stabilizes N-degron-carrying ER chaperones. (a) Cartoon illustrating the generation of N-degron carrying ER chaperones upon induction of ER stress and involvement of N-degron carrying E HSPA5 in the regulation of autophagy via activation of the N-recognin SQSTM1/p62. (b) Schematic illustration of the Ub-X-HSPA5-MYC and Ub-E CALR-GFP reporters. (c) PLpro promotes the stabilization of the E HSPA5 and R-E HSPA5 reporters. HEK293T cells were transiently cotransfected with the FLAG-ev/PLpro/PLpro mut and Ub-R E HSPA5-MYC or Ub-E HSPA5-MYC plasmids. As a control for proteasome-and lysosome-dependent degradation, the FLAGev transfected cells were treated overnight with 100 nM epoxomicin or 100 nM Baf A1, respectively. The expression of the R-E HSPA5 was analyzed 24 h posttransfection by probing western blots with the indicated antibodies. Representative blots from one out of three independent experiments are shown. (d) The intensities of the R-E HSPA5 bands were quantified by densitometry in three independent experiments. The mean ± SD relative intensity of the R-E HSPA5 bands in FLAG-PLpro/PLpro mut transfected or epoxomicin/Baf A1 treated cells versus FLAG-ev transfected cells is shown. Significance was calculated by unpaired two-tailed Student t-test. (e) PLpro deubiquitinates R-E HSPA5. HEK293T cells were transiently cotransfected with Ub-R-E HSPA5-MYC and FLAG-ev/PLpro/PLpro mut . Cell lysates were immunoprecipitated with anti-MYC agarose beads, and western blots were probed with the indicated antibodies. Blots from one representative experiment out of two are shown in the figure. (f) PLpro stabilizes N-degron carrying CALR. HEK293T cells were cotransfected with FLAG-ev/PLpro/PLpro mut and the Ub-E CALR-GFP. Cell lysates were immunoprecipitated with a GFP antibody, followed by capture with protein G-coated sepharose beads. An isotype-matched IgG control was included in the immunoprecipitation to verify specificity. Western blots were probed with the indicated antibodies. Blots from one representative experiment out of three are shown in the figure. (g) The intensities of the GFP bands were quantified by densitometry in three independent experiments. The mean ± SD, the relative intensity of the GFP bands in FLAG-PLpro/PLpro mut versus FLAG-ev transfected cells is shown. Significance was calculated by unpaired two-tailed Student's t-tests.
Figure 5. PLpro enhances the R-E HSPA5-driven formation of SQSTM1/p62 aggregates. (a) Reciprocal immunoprecipitation illustrating the interaction of PLpro with R-E HSPA5 and SQSTM1/p62. Equal aliquots of HEK293T lysates cotransfected with FLAG-ev/PLpro/PLpro mut and Ub-R-E HSPA5-MYC were immunoprecipitated with anti-FLAG, anti-MYC or anti-SQSTM1/p62 antibody-coated beads. An isotype-matched antibody was used as a control. Western blots were probed with the indicated antibodies. Blots from one representative experiment out of three are shown in the figure. (b) Catalytically active PLpro enhances the formation of large SQSTM1/p62 aggregates in cells expressing R-E HSPA5. Endogenous SQSTM1/p62 (red) was detected by immunofluorescence in control and Dox-treated U2OS Emerald PLpro/ PLpro mut cells and transfected with the R-E HSPA5-MYC reporter (blue). Images from one representative experiment out of four are shown. (c, d) PLpro enhances the number and size of SQSTM1/p62 aggregates in R-E HSPA5-expressing cells. The number and size of SQSTM1/p62 puncta were determined using the Fiji software and its analysis particle function from 75 confocal images containing approximately 1000 cells per condition. For each image, the brightness and contrast were adjusted to reduce the background noise, and particles of size >0.049 μm 2 were scored as puncta. (c) The data are presented as fold change in cells expressing R-E HSPA5 and PLpro/PLpro mut relative to cells expressing R-E HSPA5 alone in three (PLpro mut ) or four (PLpro) independent experiments. Significance was calculated by unpaired twotailed Student's t-tests. (d) Microsoft Excell was used to categorize the particles based on size. The data are represented as a percentage (%) of the total number of puncta. Data from the experiment in Figure 5B are shown. Similar results were obtained in three independent experiments. Scale bar: 10 µm.
Figure 6. PLpro recruits components of the autophagosome biogenesis machinery to large SQSTM1/p62 aggregates. (a) FLAG immunoprecipitates of HEK293T cells transfected with FLAG-ev/PLpro/PLpro mut in the presence or absence of co-transfected Ub-R-E HSPA5-MYC were probed with the indicated antibodies. Western blots from one representative experiment out of three are shown in the figure. (b) Representative confocal images illustrating the colocalization of ATG9A and WIPI2 with large SQSTM1/p62 aggregates. Scale bar: 10 µm.
Figure 7. Catalytically active PLpro inhibits the formation of LC3-II. (a) Control and doxycycline-treated U2OS cells stably transfected with plasmids expressing inducible Emerald-ev/PLpro/PLpro mut were kept untreated or treated overnight with 100 nM Baf A1 before analysis of protein expression by probing western blots with the indicated antibodies. Blots from one representative experiment out of four are shown. (b) Quantification of the LC3-specific bands. The data are presented as LC3-II:LC3-I ratios in four independent experiments. Significance was calculated by unpaired two-tailed Student's t-tests.
Regulation of N-degron recognin-mediated autophagy by the SARS-CoV-2 PLpro ubiquitin deconjugase

January 2025

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22 Reads

Viral proteases play critical roles in the host cell and immune remodeling that allows virus production. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) papain-like protease (PLpro) encoded in the large nonstructural protein 3 (Nsp3) also possesses isopeptidase activity with specificity for ubiquitin and ISG15 conjugates. Here, we interrogated the cellular interactome of the SARS-CoV-2 PLpro catalytic domain to gain insight into the putative substrates and cellular functions affected by the viral deubiquitinase. PLpro was detected in protein complexes that control multiple ubiquitin and ubiquitin-like (UbL) regulated signaling and effector pathways. By restricting the analysis to cytosolic and membrane-associated ubiquitin ligases, we found that PLpro interacts with N-recognin ubiquitin ligases and preferentially rescues type I N-degron substrates from protea-somal degradation. PLpro stabilized N-degron carrying HSPA5/BiP/GRP78, which is arginylated in the cytosol upon release from the endoplasmic reticulum (ER) during ER stress, and enhanced the Arg-HSPA5-driven oligomerization of the N-recognin SQSTM1/p62 that serves as a platform for phago-phore assembly. However, while in addition to Arg-HSPA5 and SQSTM1/p62, ATG9A, WIPI2, and BECN1/Beclin 1 were detected in PLpro immunoprecipitates, other components of the autophago-some biogenesis machinery, such as the ATG12-ATG5-ATG16L1 complex and MAP1LC3/LC3 were absent, which correlated with proteolytic inactivation of ULK1, impaired production of lipidated LC3-II, and inhibition of reticulophagy. The findings highlight a novel mechanism by which, through the reprogramming of autophagy, the PLpro deubiquitinase may contribute to the remodeling of intracellular membranes in coronavirus-infected cells.


Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival

January 2025

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26 Reads

Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of cellular material. Maintenance of lysosomal integrity is essential for cellular homeostasis and lysosomal membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes are repaired or degraded via lysophagy, during which glycans, exposed on ruptured lysosomal membranes, are recognized by galectins leading to K48- and K63-linked poly-ubiquitination (poly-Ub) of lysosomal proteins followed by recruitment of the macroautophagic/autophagic machinery and degradation. Linear (M1) poly-Ub, catalyzed by the linear ubiquitin chain assembly complex (LUBAC) E3 ligase and removed by OTULIN (OTU deubiquitinase with linear linkage specificity) exerts important functions in immune signaling and cell survival, but the role of M1 poly-Ub in lysosomal homeostasis remains unexplored. Here, we demonstrate that L-leucyl-leucine methyl ester (LLOMe)-damaged lysosomes accumulate M1 poly-Ub in an OTULIN- and K63 Ub-dependent manner. LMP-induced M1 poly-Ub at damaged lysosomes contributes to lysosome degradation, recruits the NFKB (nuclear factor kappa B) modulator IKBKG/NEMO and locally activates the inhibitor of NFKB kinase (IKK) complex to trigger NFKB activation. Inhibition of lysosomal degradation enhances LMP- and OTULIN-regulated cell death, indicating pro-survival functions of M1 poly-Ub during LMP and potentially lysophagy. Finally, we demonstrate that M1 poly-Ub also occurs at damaged lysosomes in primary mouse neurons and induced pluripotent stem cell-derived primary human dopaminergic neurons. Our results reveal novel functions of M1 poly-Ub during lysosomal homeostasis, LMP and degradation of damaged lysosomes, with important implications for NFKB signaling, inflammation and cell death.Abbreviation: ATG: autophagy related; BafA1: bafilomycin A1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CRISPR: clustered regularly interspaced short palindromic repeats; CHUK/IKKA: component of inhibitor of nuclear factor kappa B kinase complex; CUL4A-DDB1-WDFY1: cullin 4A-damage specific DNA binding protein 1-WD repeat and FYVE domain containing 1; DGCs: degradative compartments; DIV: days in vitro; DUB: deubiquitinase/deubiquitinating enzyme; ELDR: endo-lysosomal damage response; ESCRT: endosomal sorting complex required for transport; FBXO27: F-box protein 27; GBM: glioblastoma multiforme; IKBKB/IKKB: inhibitor of nuclear factor kappa B kinase subunit beta; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; IKK: inhibitor of NFKB kinase; iPSC: induced pluripotent stem cell; KBTBD7: kelch repeat and BTB domain containing 7; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LCD: lysosomal cell death; LGALS: galectin; LMP: lysosomal membrane permeabilization; LLOMe: L-leucyl-leucine methyl ester; LOP: loperamide; LUBAC: linear ubiquitin chain assembly complex; LRSAM1: leucine rich repeat and sterile alpha motif containing 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NBR1: NBR1 autophagy cargo receptor; NFKB/NF-κB: nuclear factor kappa B; NFKBIA/IĸBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; OPTN: optineurin; ORAS: OTULIN-related autoinflammatory syndrome; OTULIN: OTU deubiquitinase with linear linkage specificity; RING: really interesting new gene; RBR: RING-in-between-RING; PLAA: phospholipase A2 activating protein; RBCK1/HOIL-1: RANBP2-type and C3HC4-type zinc finger containing 1; RNF31/HOIP: ring finger protein 31; SHARPIN: SHANK associated RH domain interactor; SQSTM1/p62: sequestosome 1; SR-SIM: super-resolution-structured illumination microscopy; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TH: tyrosine hydroxylase; TNF/TNFα: tumor necrosis factor; TNFRSF1A/TNFR1-SC: TNF receptor superfamily member 1A signaling complex; TRIM16: tripartite motif containing 16; Ub: ubiquitin; UBE2QL1: ubiquitin conjugating enzyme E2 QL1; UBXN6/UBXD1: UBX domain protein 6; VCP/p97: valosin containing protein; WIPI2: WD repeat domain, phosphoinositide interacting 2; YOD1: YOD1 deubiquitinase.



Reconsidering the selectivity of bulk autophagy: cargo hitchhiking specifies cargo for degradation

December 2024

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63 Reads

Bulk macroautophagy/autophagy, typically induced by starvation, is generally thought to isolate cytosolic components for degradation in a non-selective manner. Despite the fundamental nature of the eukaryotic degradation pathway, the question of what cargo is isolated by autophagy has remained unaddressed for over 30 years. We recently employed mass spectrometry to analyze the contents of isolated autophagic bodies. In the process of these experiments, we uncovered Hab1 (Highly enriched in Autophagic Bodies 1), a novel protein that is delivered extremely preferentially via autophagy. We report that Hab1 is a novel receptor protein, the N-terminus of which binds Atg8-PE, whereas the C-terminus binds ribosomes. Surprisingly, detailed biochemical and microscopic analyses revealed that ribosome-bound Hab1 is preferentially delivered to the vacuole by "'hitchhiking'" on phagophores/isolation membranes that form during bulk autophagy. This is a completely different mechanism of cargo selection that differs from previous descriptions of selective autophagy, in which the cargo-specific receptor proteins initiate phagophore membrane formation via scaffold proteins such as Atg11. We propose that cargo hitchhiking allows for the specification of cargo during bulk autophagy, which is otherwise a non-selective process.


Journal metrics


14.6 (2023)

Journal Impact Factor™


31%

Acceptance rate


21.3 (2023)

CiteScore™


10 days

Submission to first decision


2.227 (2023)

SNIP


4.035 (2023)

SJR

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