Immune regulators PALS-25 and PALS-22 localize to mitochondria and regulate mitochondrial fragmentation in C. elegans

The nematode C. elegans controls immunity against intracellular pathogens such as microsporidia, using the pals gene family, which has expanded in C. elegans compared to mammals. pals-22 is a negative regulator that restrains pals-25, which serves as a positive regulator of immunity. pals-22 and pals-25 encode proteins that bind each other and can act in the intestine and epidermis, but their subcellular localization and mechanism of action have not been described. Here, we show that PALS-22 and PALS-25 proteins localize to mitochondria, with PALS-25 being required for PALS-22 localization to mitochondria. The C-terminus of PALS-25 directs mitochondrial localization, and the N-terminus is required for signaling. The loss of PALS-22 causes mitochondrial fragmentation, which occurs after activating the intracellular pathogen response (IPR), a transcriptional program induced by intracellular infection. Mitochondrial fragmentation induced by knockdown of fission/fusion factors increases resistance against microsporidia infection. Thus, the PALS-22/25-mediated fragmentation of mitochondria enhances resistance against intracellular infection.