BECN1s, a short splice variant of BECN1, functions in mitophagy

Abstract

These authors contributed equally to this work.Keywords: BECN1, BECN1s, mitochondrial depolarization, mitophagy, starvation Abbreviations: Atg, autophagy-related; bp, base pairs; BECN1s, BECN1 short isoform; CCCP, carbonyl cyanide m-chlorophenylhydrazone; EBSS, Earle's balanced salt solution; ECD, evolutionarily conserved domain; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; PtdIns3K, class III phosphatidylinositol 3-kinaseMitochondria selective autophagy, known as mitophagy, plays a pivotal role in several biological processes, such as elimination of the damaged mitochondria, removal of the mitochondria from immature red blood cells and sperm. The defects in mitophagy are associated with a wide spectrum of human diseases, including neurodegenerative disease, aging, cardiac disease and autoimmune disease. However, the mechanism underlying mitophagy remains largely unclear. Here, we report the characterization of a novel splice variant of BECN1/Beclin 1, BECN1s, which is produced by an alternative splicing mechanism. BECN1s is primarily associated with the outer-membrane of mitochondria. Unlike unspliced BECN1, which is essential for nonselective macroautophagy induction, BECN1s is indispensible for mitochondria-selective autophagy. Furthermore, BECN1s plays an important role in starvation-and membrane depolarization-induced mitophagy. Taken together, our findings broaden the view of BECN1 as an important regulator in autophagy, and implicate BECN1s as a specific mitophagy mediator.

Alternative splicing and cell survival: from tissue homeostasis to disease

“…102,103 AS converts BECN1 from an inducer of nonselective macroautophagy to a regulator of mitochondriaselective autophagy. 105 BECN1s, a shorter splice variant originating from skipping of exons 10 and 11, selectively localizes in the outer membrane of mitochondria and contributes to mitophagy in response to starvation or mitochondrial membrane depolarization. 105 New splice variants were also identified in members of the autophagy-related gene 8 (ATG8) family (LC3B, GABARAP and GABARAPL1).…”

“…105 BECN1s, a shorter splice variant originating from skipping of exons 10 and 11, selectively localizes in the outer membrane of mitochondria and contributes to mitophagy in response to starvation or mitochondrial membrane depolarization. 105 New splice variants were also identified in members of the autophagy-related gene 8 (ATG8) family (LC3B, GABARAP and GABARAPL1). 106 They encode proteins that are not integrated in the autophagosomes, suggesting that they could limit autophagy.…”

The Protective Roles of ROS‐Mediated Mitophagy on 125I Seeds Radiation Induced Cell Death in HCT116 Cells

“…Mitophagy, which refers to the selective removal of damaged or unwanted mitochondria, is crucial for mitochondrial quality control following stresses such as starvation, photo damage, hypoxia, and ROS production [15]. Certain physiological stresses can induce mitochondrial damage, which can cause oxidative stress and cell death triggered by the production of ROS from the mitochondrial electron transport chain (ETC).…”

Caspase mediated beclin‐1 dependent autophagy tuning activity and apoptosis promotion by surface modified hausmannite nanoparticle

“…We have observed that phenomena of Beclin‐1 exclusive cleavage/splice, that could be a short noval varient of Beclin‐1, results in the subsequent formation of both the Beclin‐1‐PI3KC3 complex and its derivative, which are autophagic. BH3 domain of Beclin‐1 subsequently interacts with Bcl‐2 protein and act as anti‐apoptotic feature.…”