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Interactomic analysis reveals a homeostatic role for the HIV restriction factor TRIM5α in mitophagy

Bhaskar Saha1, Michelle Salemi2, Geneva L Williams3

  • 1Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.

Cell Reports
|May 11, 2022
PubMed

Insights

The protein TRIM5-alpha (TRIM5α) is essential for mitophagy, a cellular process for clearing damaged mitochondria. This discovery reveals a new homeostatic role for TRIM5α beyond its known antiviral functions.

Area of Science:

  • Cellular Biology
  • Immunology
  • Biochemistry

Background:

  • The protein TRIM5-alpha (TRIM5α) is recognized for its role in antiretroviral defense, but its precise mechanisms of action remain incompletely understood.
  • Mitochondrial dysfunction is implicated in various human diseases, highlighting the importance of mitochondrial quality control mechanisms like mitophagy.

Purpose of the Study:

  • To identify TRIM5α-interacting proteins and elucidate the mechanisms underlying TRIM5α's functions using APEX2-based proteomics.
  • To investigate the potential role of TRIM5α in mitophagy and mitochondrial homeostasis.

Main Methods:

  • Employed APEX2-based proximity-dependent biotinylation followed by mass spectrometry to identify TRIM5α-interacting partners.
  • Utilized cell-based assays to assess mitophagy pathways, mitochondrial function, and cellular responses to mitochondrial damage in TRIM5α knockout and wild-type cells.
  • Investigated the role of TRIM5α's ubiquitin ligase activity in mitophagy.

Main Results:

  • Proteomics identified TRIM5α-interacting proteins involved in antiviral defense and, notably, linked TRIM5α to mitophagy pathways.
  • TRIM5α is crucial for both Parkin-dependent and -independent mitophagy, recruiting autophagy regulators to damaged mitochondria.
  • TRIM5α's ubiquitin ligase activity is necessary for its role in mitophagy; cells lacking TRIM5α exhibit impaired mitochondrial function and increased susceptibility to mitochondrial damage-induced stress.

Conclusions:

  • TRIM5α plays a critical, previously unrecognized homeostatic role in regulating mitophagy and maintaining mitochondrial quality control.
  • These findings expand the known functions of TRIM5α beyond antiviral defense, suggesting its involvement in cellular health and disease.
Keywords:
APEX2CP: Cell biologyCP: ImmunologyER-mitochondria contact siteHIV-1TRIM5αULK1 complexautophagyinflammationmitochondrial metabolismproteomicstripartite motif

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