Recent studies have shown that mitochondria play key roles in mammalian immunity. C. elegans mitochondria also modulate resistance against pathogenic bacterial infection [1-4], suggesting a conserved role of mitochondria in immunity. However, specific mitochondrial components that regulate immunity at the organismal level remain largely unknown. Here, we identified mitochondrial proteins crucial for immunity by using C. elegans and P. aeruginosa (PA14) as an in vivo host-pathogen model. We performed an RNAi screen targeting 313 genes that encode evolutionarily conserved mitochondrial proteins. We identified 16 genes that reproducibly altered the survival of C. elegans upon PA14 infection. Among them,
hsp-60, a major mitochondria-protective chaperone, was necessary and sufficient for enhancing resistance upon PA14 infection. We showed that intestine- or neuron-specific
hsp-60 knockdown increased the susceptibility of animals to PA14. Genetic inhibition of the upstream regulators of HSP-60, including
dve-1,
ubl-5 or
atfs-1, reduced the survival of worms upon PA14 infection but
haf-1 mutation did not. We then determined the interaction between HSP-60 and PMK-1/p38 MAP kinase signaling, a key anti-bacterial immune pathway in C. elegans [5]. We showed that knockdown and overexpression of
hsp-60 down- and up-regulated PMK-1, respectively.
dve-1 and
ubl-5 RNAi down-regulated PMK-1 signaling as well, whereas
atfs-1 or
haf-1 mutations did not.
pmk-1 mutations largely suppressed the resistance to PA14 conferred by
hsp-60 overexpression. These data suggest that the DVE-1/UBL-5/HSP-60 axis of mitochondrial chaperone function confers immunity via modulating PMK-1 signaling. Our data imply that HSP-60 may exert immune function by relaying signals from mitochondria to cytosolic
p38 MAP kinase. [1] Hwang et al., 2014, PNAS, [2] Liu et al., 2014, Nature, [3] Pellegrino et al., 2014, Nature, [4] Kirienko et al., 2015, PNAS, [5] Kim et al., 2002, Science.