The overall objective of this project is to determine the molecular mechanisms by which Bif-1 activates autophagy and suppresses tumorigenesis. Autophagy, an evolutionarily conserved """"""""self- eating"""""""" process, is activated in response to environmental and cellular stresses and plays a fundamental role in maintaining normal cellular homeostasis by delivering unfolded proteins, damaged organelles, and microbial pathogens to lysosomes for degradation. Dysregulation of this cellular self-digestion process can have profound consequences and most likely plays a major role in many types of diseases, including cancer, autoimmune diseases, and neurodegenerative disorders. To date, many autophagy-related (Atg) genes have been identified by independent genetic screens for autophagy-defective mutants in yeast;however, the molecular machinery required for the biogenesis of autophagosomes in mammalian systems has yet to be determined. We have recently discovered that Bif-1 interacts with Beclin 1 through UVRAG and is required for the biogenesis of autophagosomes. Bif-1, also known as SH3GLB1 or endophilin B1, was originally discovered as a Bax-binding protein that contains an amino-terminal N-BAR domain and a carboxy-terminal SH3 domain and demonstrates membrane binding and bending activities. Although the SH3 domain of Bif-1 is sufficient for binding to UVRAG, the N-BAR domain is indispensable for Bif-1 to induce autophagosome formation. Therefore, it is possible that Bif-1 interacts with Beclin 1 through UVRAG at the isolation membrane, or phagophore, during autophagy to regulate vesicle nucleation by inducing membrane curvature through its N- BAR domain.
Specific Aim 1 will test this possibility. While our in vitro studies clearly demonstrated the vital role Bif-1 plays in autophagosome formation, the majority of Bif-1 knockout mice, unlike Atg-deficient mice, developed normally. This phenotypic discrepancy suggests that an unknown factor(s) exists in specific tissues that functionally compensate for the lack of Bif-1 during embryonic and neonatal development. A possible candidate is the Bif-1 homologue endophilin B2. Our preliminary results revealed that endophilin B2 also interacts with Beclin 1 as well as UVRAG and can restore autophagosome formation in Bif-1 deficient cells.
Specific Aim 2 will examine whether endophilin B2 shares a function redundant with Bif-1 in the control of autophagy. Moreover, we found that Bif-1 ablation significantly enhances the development of spontaneous tumors in mice. Since loss of Bif-1 also suppresses Bax/Bak activation and mitochondrial apoptosis, Specific Aim 3 will determine whether Bif-1 induces autophagosome formation and suppresses tumorigenesis independently of its interaction with Bax. We believe that successful implementation of this research will not only gain novel insight into the origin of isolation membranes and the molecular mechanism responsible for autophagic vesicle nucleation and expansion, but will also contribute to the establishment of new strategies for the prevention and treatment of cancer through manipulation of autophagy.
We believe that successful implementation of this research will not only gain novel insight into the origin of isolation membranes and the molecular mechanism responsible for autophagic vesicle nucleation and expansion, but will also contribute to the establishment of new strategies for the prevention and treatment of cancer through manipulation of autophagy.
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|Serfass, Jacob M; Takahashi, Yoshinori; Zhou, Zhixiang et al. (2017) Endophilin B2 facilitates endosome maturation in response to growth factor stimulation, autophagy induction, and influenza A virus infection. J Biol Chem 292:10097-10111|
|Takahashi, Yoshinori; Tsotakos, Nikolaos; Liu, Ying et al. (2016) The Bif-1-Dynamin 2 membrane fission machinery regulates Atg9-containing vesicle generation at the Rab11-positive reservoirs. Oncotarget 7:20855-68|
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|Takahashi, Yoshinori; Hori, Tsukasa; Cooper, Timothy K et al. (2013) Bif-1 haploinsufficiency promotes chromosomal instability and accelerates Myc-driven lymphomagenesis via suppression of mitophagy. Blood 121:1622-32|
|Takahashi, Yoshinori; Young, Megan M; Serfass, Jacob M et al. (2013) Sh3glb1/Bif-1 and mitophagy: acquisition of apoptosis resistance during Myc-driven lymphomagenesis. Autophagy 9:1107-9|
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|Zhang, Yi; Cheng, Yan; Ren, Xingcong et al. (2012) Dysfunction of nucleus accumbens-1 activates cellular senescence and inhibits tumor cell proliferation and oncogenesis. Cancer Res 72:4262-75|
|Ren, Tong; Dong, Wen; Takahashi, Yoshinori et al. (2012) HTLV-2 Tax immortalizes human CD4+ memory T lymphocytes by oncogenic activation and dysregulation of autophagy. J Biol Chem 287:34683-93|
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