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

The protein TRIM5α has multiple roles in antiretroviral defense, but the mechanisms underlying TRIM5α action are unclear. Here, we employ APEX2-based proteomics to identify TRIM5α-interacting partners. Our proteomics results connect TRIM5 to other proteins with actions in antiviral defense. Additionally, they link TRIM5 to mitophagy, an autophagy-based mode of mitochondrial quality control that is compromised in several human diseases. We find that TRIM5 is required for Parkin-dependent and -independent mitophagy pathways where TRIM5 recruits upstream autophagy regulators to damaged mitochondria. Expression of a TRIM5 mutant lacking ubiquitin ligase activity is unable to rescue mitophagy in TRIM5 knockout cells. Cells lacking TRIM5 show reduced mitochondrial function under basal conditions and are more susceptible to immune activation and death in response to mitochondrial damage than are wild-type cells. Taken together, our studies identify a homeostatic role for a protein previously recognized exclusively for its antiviral actions. [Display omitted] • Unbiased proteomic analysis reveals that TRIM5α associates with mitochondria • TRIM5α links upstream autophagy proteins with markers of damaged mitochondria • Mitophagy is compromised in TRIM5α knockout cells • TRIM5α knockout exacerbates the cellular impacts of mitochondrial damage The protein TRIM5α is well known for its roles in antiretroviral defense. Saha et al. show that TRIM5α also has key homeostatic functions. They report that TRIM5α helps to maintain mitochondrial quality control by enabling the autophagy-dependent removal of damaged mitochondria (mitophagy). [ABSTRACT FROM AUTHOR]