Jnk2 promotes stress-induced mitophagy and suppresses inflammasome activation by targeting smARF for degradation

Mitophagy is essential for cellular homeostasis but the regulatory mechanism is largely unknown. Here we report that the kinase Jnk2 is required for stress-induced mitophagy. Jnk2 promoted ubiquitination and proteasomal degradation of small mitochondrial form of ARF (smARF). Loss of Jnk2 led to accumulation of smARF, which in turn induced excessive autophagic activity, resulting in lysosomal degradation of the mitophagy adaptor p62 in the steady state. The depletion of p62 prevented Jnk2-deficient cells from mounting mitophagy upon stress. Jnk2-deficient mice displayed defective mitophagy, resulting in tissue damage under hypoxic stress, as well as hyperactivation of inflammasome and increased mortality in sepsis. Our finding defines a unique mechanism of maintaining immune homeostasis that protects the host from tissue damage and mortality.