Bcl2-associated athanogene 3 interactome analysis reveals a new role in modulating proteasome activity

Ying Chen, Li Na Yang, Li Cheng, Shun Tu, Shu Juan Guo, Huang Ying Le, Qian Xiong, Ran Mo, Chong Yang Li, Jun Seop Jeong, Lizhi Jiang, Seth Blackshaw, Li Jun Bi, Heng Zhu, Sheng Ce Tao, Feng Ge

Research output: Contribution to journalArticlepeer-review

Abstract

Bcl2-associated athanogene 3(BAG3), a member of the BAG family of co-chaperones, plays a critical role in regulating apoptosis, development, cell motility, autophagy, and tumor metastasis and in mediating cell adaptive responses to stressful stimuli. BAG3 carries a BAG domain, a WW domain, and a proline-rich repeat (PXXP), all of which mediate binding to different partners. To elucidate BAG3's interaction network at the molecular level, we employed quantitative immunoprecipitation combined with knockdown and human proteome microarrays to comprehensively profile the BAG3 interactome in humans. We identified a total of 382 BAG3-interacting proteins with diverse functions, including transferase activity, nucleic acid binding, transcription factors, proteases, and chaperones, suggesting that BAG3 is a critical regulator of diverse cellular functions. In addition, we characterized interactions between BAG3 and some of its newly identified partners in greater detail. In particular, bioinformatic analysis revealed that the BAG3 interactome is strongly enriched in proteins functioning within the proteasome-ubiquitination process and that compose the proteasome complex itself, suggesting that a critical biological function of BAG3 is associated with the proteasome. Functional studies demonstrated that BAG3 indeed interacts with the proteasome and modulates its activity, sustaining cell survival and underlying resistance to therapy through the down-modulation of apoptosis. Taken as a whole, this study expands our knowledge of the BAG3 interactome, provides a valuable resource for understanding how BAG3 affects different cellular functions, and demonstrates that biologically relevant data can be harvested using this kind of integrated approach.

Original languageEnglish (US)
Pages (from-to)2804-2819
Number of pages16
JournalMolecular and Cellular Proteomics
Volume12
Issue number10
DOIs
StatePublished - Oct 2013

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology

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