The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses. Jung et al.

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The human body reacts to tissue damage by generating damage-associated molecular patterns (DAMPs) that activate sterile immune responses. To date, little is known about how DAMPs are removed to avoid excessive immune responses. Here, we show that proteasomal dysfunction induces the release of mitochondrial DNA (mtDNA) as a DAMP that activates the cGAS-STING pathway and is subsequently degraded through the N-degron pathway. In the resolution phase of sterile immune responses, DNA-PK senses cytosolic mtDNA and activates N-terminal (Nt-) arginylation by ATE1 R-transferases. The substrates of Nt-arginylation include the molecular chaperone BiP/GRP78 retrotranslocated from the endoplasmic reticulum (ER). R-BiP, the Nt-arginylated species of BiP, is associated with cytosolic mtDNA to accelerate its targeting to autophagic membranes for lysosomal degradation. Thus, cytosolic mtDNA activates the N-degron pathway to facilitate its own degradation to form a negative feedback loop, by which the cell can turn off sterile immune responses in a right time.

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