Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 to selectively remove endoplasmic reticulum and mitochondria via autophagy
ABSTRACT Autophagy plays an important role in cellular quality control and is responsible for removing protein aggregates and dysfunctional organelles. Bnip3 is an atypical BH3-only protein that is known to cause mitochondrial dysfunction and cell death. Interestingly, Bnip3 can also protect against cell death by inducing mitochondrial autophagy. The mechanism for this process, however, remains poorly understood. Bnip3 contains a C-terminal transmembrane domain that is essential for homodimerization and proapoptotic function. In this study, we show that homodimerization of Bnip3 is also a requirement for induction of autophagy. Several Bnip3 mutants that do not interfere with its mitochondrial localization but disrupt homodimerization failed to induce autophagy in cells. In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). To investigate the effects of Bnip3 at mitochondria or the ER on autophagy, Bnip3 was targeted specifically to each organelle by substituting the Bnip3 transmembrane domain with that of Acta or cytochrome b(5). We found that Bnip3 enhanced autophagy in cells from both sites. We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. The clearance of these organelles was mediated in part via binding of Bnip3 to LC3 on the autophagosome. Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. Our data indicate that Bnip3 regulates the apoptotic balance as an autophagy receptor that induces removal of both mitochondria and ER.
- SourceAvailable from: Yung-Hsiang Chen
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- "Recent studies suggest that autophagy may play an important role not only in the regulation of cancer development and progression but also in determining the response of cancer cells to anticancer therapy   . Subsequent studies have also identified microtubuleassociated protein 1 light chain 3 (LC3)    and Beclin- 1    as essential markers for autophagy. There are three isoforms of LC3, namely, LC3A, LC3B, and LC3C. "
ABSTRACT: Glioblastoma multiforme is one of the most serious malignant brain tumors and is characterized by resistance to chemotherapy and radiation therapy. Recent studies suggest that autophagy may play an important role not only in the regulation of cancer development and progression but also in determining the response of cancer cells to anticancer therapy. The purpose of the present study was to assess the relationship between protein expressions of two autophagy markers, LC3B and Beclin-1, with clinical parameters in astrocytoma patients. Furthermore, the expression of CD133, a marker of the cancer stem-like cells, in astrocytoma patients was also investigated. A total of 106 thin-section slides were retrospectively collected from astrocytoma patients. LC3B, but not Beclin-1, protein expression was found to significantly correlate with resistance to radiation- or chemotherapy. In addition, high intensity of LC3B staining was predictive of poor prognosis. Furthermore, survival time of patients with high-level expression in both CD133 and LC3B was significantly shorter than those with weak expression in both CD133 and LC3B. These results suggest that astrocytoma cancer stem-like cells together with enhanced autophagy may cause resistance to radiation therapy/chemotherapy and that targeting the cancer stem-like cell in astrocytoma may offer a viable therapeutic approach.BioMed Research International 05/2014; 2014:723176. DOI:10.1155/2014/723176 · 2.71 Impact Factor
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- "Several mitophagy receptors have been reported to mediate mitophagy thus far, including ATG32 in yeast (Kanki et al., 2009; Okamoto et al., 2009), NIX/BNIP3L (Novak et al., 2010; Sandoval et al., 2008) for red blood cell maturation, and BNIP3 (Hanna et al., 2012) for the selective removal of endoplasmic reticulum and mitochondria under conditions of hypoxia. We recently identified FUNDC1 as a specific receptor involved in mitophagy in mammalian cells (Liu et al., 2012). "
ABSTRACT: Mitochondrial autophagy, or mitophagy, is a major mechanism involved in mitochondrial quality control via selectively removing damaged or unwanted mitochondria. Interactions between LC3 and mitophagy receptors such as FUNDC1, which harbors an LC3-interacting region (LIR), are essential for this selective process. However, how mitochondrial stresses are sensed to activate receptor-mediated mitophagy remains poorly defined. Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation. Our results reveal a mechanistic signaling pathway linking mitochondria-damaging signals to the dephosphorylation of FUNDC1 by PGAM5, which ultimately induces mitophagy.Molecular cell 04/2014; 54(3). DOI:10.1016/j.molcel.2014.02.034 · 14.46 Impact Factor
- "Subsequently, ubiquitylation of the bacterial surface provides a key signal for the recruitment of three xenophagy receptors NDP52, p62/SQSTM1 and optineurin (Thurston et al., 2009; Wild et al., 2011; Zheng et al., 2009). In contrast, mitophagy receptors (Atg32 in yeast; BNIP3, BNIP3L and FUNDC1 in mammals) are outer mitochondrial membrane proteins that are already placed and primed for autophagic clearance of mitochondria (Hanna et al., 2012; Kanki et al., 2009; Liu et al., 2012; Novak et al., 2010; Okamoto et al., 2009). However, during Parkin-mediated mitophagy, outer mitochondrial surface proteins, such as VDAC1 or mitofusin, become ubiquitylated and BNIP3 has been shown to affect the translocation of Parkin to stressed mitochondria. "
Article: The LC3 interactome at a glance[Show abstract] [Hide abstract]
ABSTRACT: Continuous synthesis of all cellular components requires their constant turnover in order for a cell to achieve homeostasis. To this end, eukaryotic cells are endowed with two degradation pathways - the ubiquitin-proteasome system and the lysosomal pathway. The latter pathway is partly fed by autophagy, which targets intracellular material in distinct vesicles, termed autophagosomes, to the lysosome. Central to this pathway is a set of key autophagy proteins, including the ubiquitin-like modifier Atg8, that orchestrate autophagosome initiation and biogenesis. In higher eukaryotes, the Atg8 family comprises six members known as the light chain 3 (LC3) or γ-aminobutyric acid (GABA)-receptor-associated protein (GABARAP) proteins. Considerable effort during the last 15 years to decipher the molecular mechanisms that govern autophagy has significantly advanced our understanding of the functioning of this protein family. In this Cell Science at a Glance article and the accompanying poster, we present the current LC3 protein interaction network, which has been and continues to be vital for gaining insight into the regulation of autophagy.Journal of Cell Science 12/2013; 127(1). DOI:10.1242/jcs.140426 · 5.33 Impact Factor