RT Journal Article
SR Electronic
T1 Interactomic analysis reveals a new homeostatic role for the HIV restriction factor TRIM5α in mitophagy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.20.457143
DO 10.1101/2021.08.20.457143
A1 Bhaskar Saha
A1 Michelle Salemi
A1 Geneva L Williams
A1 Michael L Paffett
A1 Brett Phinney
A1 Michael A Mandell
YR 2021
UL http://biorxiv.org/content/early/2021/08/20/2021.08.20.457143.abstract
AB The protein TRIM5α has multiple roles in anti-retroviral defense, but the mechanisms underlying TRIM5α action are unclear. Here, we used an APEX2-based proteomics approach to identify TRIM5α-interacting proteins. Analysis of the TRIM5α interactome found proteins participating in a wide variety of cellular functions including regulating antiviral signaling pathways. We used this data set to uncover a novel role for TRIM5α in mitophagy, an autophagy-based mode of mitochondrial quality control that is compromised in multiple human diseases. Mitochondrial damage triggered the relocalization of TRIM5α to ER-mitochondria contact sites where TRIM5α colocalized with markers of autophagy initiation and autophagosome biogenesis. Furthermore, we found that TRIM5α knockout attenuated both Parkin-dependent and Parkin-independent mitophagy by preventing the recruitment of autophagy regulators FIP200 and ATG13 to unhealthy mitochondria. Finally, TRIM5α knockout cells showed reduced mitochondrial function under basal conditions and were more susceptible to uncontrolled immune activation and cell death in response to mitochondrial damage than were wild type cells. Taken together, our studies have identified a homeostatic role for a protein previously recognized exclusively for its antiviral actions.Competing Interest StatementThe authors have declared no competing interest.