Sh3glb1/Bif-1and mitophagy

Abstract

Evasion of apoptosis, which enables cells to survive and proliferate under metabolic stress, is one of the hallmarks of cancer. We have recently reported that SH3GLB1/Bif-1 functions as a haploinsufficient tumor suppressor to prevent the acquisition of apoptosis resistance and malignant transformation during Myc-driven lymphomagenesis. SH3GLB1 is a membrane curvature-inducing protein that interacts with BECN1 though UVRAG and regulates the post-Golgi trafficking of membrane-integrated ATG9A for autophagy. At the premalignant stage, allelic loss of Sh3glb1 enhances Myc-induced chromosomal instability and results in the upregulation of anti-apoptotic proteins, including MCL1 and BCL2L1. Notably, we found that Sh3glb1 haploinsufficiency increases mitochondrial mass in overproliferated prelymphomatous Eμ-Myc cells. Moreover, loss of Sh3glb1 suppresses autophagy-dependent mitochondrial clearance (mitophagy) in PARK2/Parkin-expressing mouse embryonic fibroblasts (MEFs) treated with the mitochondrial uncoupler CCCP. Interestingly, PARK2-expressing Sh3glb1-deficient cells accumulate ER-associated immature autophagosome-like structures after treatment with CCCP. Taken together, we propose a model of mitophagy in which SH3GLB1 together with the class III phosphatidylinositol 3-kinase complex II (PIK3C3CII) (PIK3R4-PIK3C3-BECN1-UVRAG) regulates the trafficking of ATG9A-containing Golgi-derived membranes (A9(+)GDMs) to damaged mitochondria for autophagosome formation to counteract oncogene-driven tumorigenesis.

Endophilin B2 promotes inner mitochondrial membrane degradation by forming heterodimers with Endophilin B1 during mitophagy

“…Previous studies revealed that EB1 diffuses in cytoplasm and does not co-localize with mitochondria under basal conditions while aggregates into foci and translocates to mitochondria during mitophagy 8 9 . Based on the high homology of EB1 and EB2 ( Fig.…”

“…The membranes of autophagosomes are derived from various membrane sources, and subsequent processes involving autophagosomes have been shown to be associated with the Beclin-1-PI3KC3 complex 6 . The protein Endophilin B1 (EB1) has been reported to interact with Beclin-1 regulating autophagosome biogenesis 7 and associate with mitochondrial membrane promoting mitochondrial degradation 8 .…”

“…Moreover, EB1 has been shown to be capable of binding Beclin-1 through UVRAG together with PI3KC3, resulting in the formation of the UVRAG-Beclin-1-PI3KC3 complex and then inducing the generation of Golgi sourced autophagosome during autophagy 7 15 . Furthermore, owing to its ability to bind to the membrane, EB1 may promote the sequestration of damaged mitochondria by bridging the gap between autophagosome and damaged mitochondria 8 .…”

Regulation and function of mitophagy in development and cancer

“…SH3GLB1 is a member of the membrane curvaturedriving endophilin family, which regulates the post-Golgi trafficking of membrane-integrated ATG9A for autophagy. 149,150 In humans, the SH3GLB1 gene is located on chromosome 1p22, a region frequently deleted in neoplasms 151 and its expression is downregulated in a wide variety of cancers. [152][153][154][155][156] Furthermore, inhibition of endogenous expression of SH3GLB1 by RNA interference enhances the tumorigenecity of HeLa cells and SH3GLB1-knockout mice are susceptible to the development of spontaneous tumors, indicating that SH3GLB1 is indeed a novel bona fide tumor suppressor.…”

Proximity Ligation In situ Assay is a Powerful Tool to Monitor Specific ATG Protein Interactions following Autophagy Induction

“…Indeed, BECLIN-1 , BIF-1 and UVRAG , three essential autophagy genes have been classified as tumor suppressor genes and are frequently inactivated in cancer cells leading to the promotion of cell proliferation and aggressiveness. [ 8 , 9 , 10 ] Defects and mutations in autophagy genes have also been frequently observed in neurodegenerative disorders such as Alzheimer’s disease, or familial Parkinson’s disease. [ 11 ] Since then, the development of techniques to efficiently monitor autophagy levels in cell and tissue models became a challenge to better characterize autophagy protein expression, function and deregulation in these pathologies.…”