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The protein TRIM5α has multiple roles in anti-retroviral defense, but the mechanisms underlying TRIM5α action are unclear. Here, we used a 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. Mitochondrial damage triggered the relocalization of TRIM5α to mitochondria-associated endoplasmic reticulum where TRIM5α colocalized with markers of autophagy initiation and autophagosome biogenesis. Furthermore, we found that TRIM5 was required for the recruitment of the ULK1 complex and other autophagy proteins to damaged mitochondria. TRIM5 was required for both Parkin-dependent and Parkin-independent mitophagy pathways. Expression of a TRIM5 mutant that lacks ubiquitin ligase activity was unable to rescue mitophagy, indicating the importance of its enzymatic function in mitophagy. Finally, TRIM5α knockout cells showed reduced mitochondrial function and were more susceptible to immune activation and death in response to mitochondrial damage. Taken together, our studies have identified a homeostatic role for a protein previously recognized exclusively for its antiviral actions. Our identification of the TRIM5 interactome may lead to the discovery of additional new roles for TRIM5.


Poster presented at the Brain & Behavioral Health Research Day 2022



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