Kimura et al. describe how TRIM family proteins specifically target key inflammatory regulators for degradation via the autophagy pathway.
Although autophagy can nonselectively degrade cytoplasmic components by engulfing them in a double-membraned autophagosome and delivering them to lysosomes, the pathway can also act with much greater precision to target specific proteins for destruction. Specific receptors are required to link target proteins to the autophagy machinery, but only a handful of receptors have been identified to date. TRIM proteins are a large family of candidate autophagy receptors, and Kimura et al. found that several members of this family, including TRIM20 and TRIM21, induce autophagy in response to the cytokine IFN-γ.
TRIM20 targeted for degradation several subunits of the inflammasome—an activator of the inflammatory cytokine IL-1β—by linking them to multiple autophagy regulators, including the autophagy-initiating proteins Beclin 1 and ULK1, and the Atg8 family of autophagosome assembly factors. TRIM21, in contrast, coupled a similar set of autophagy regulators to the transcription factor IRF3, an activator of type I IFN responses.
TRIM21 is associated with autoimmune diseases, such as Sjögren syndrome, in which type I IFN signaling is hyperactivated, whereas mutations in the gene encoding TRIM20 are linked to familial Mediterranean fever. Several of these disease-linked mutations disrupted TRIM20’s ability to form a complex with ULK1 and induce inflammasome degradation. These TRIM protein–mediated precision autophagy pathways may therefore be crucial for limiting inflammatory responses in vivo.