HSC71 acetylation confers protection against Spiroplasma eriocheiris infection by inhibiting apoptosis and promoting ROS production in arthropods
Description
Members of the HSP70 family are indispensable components of host innate immunity, and their functions are finely tuned by post-translational modifications. However, the role of HSP70 post-translational modifications in modulating immune functions during pathogenic infection remains poorly understood. This study investigated the mechanisms that underlie acetylation modification of heat shock cognate 71 kDa protein (HSC71)-mediated resistance to intracellular pathogen Spiroplasma eriocheiris infection in crabs. Mechanistically, carnitine O-acetyltransferase (Crat) acetylated HSC71 at lysine 579 (K579), which prevented its ubiquitination by promoting the disassociation of E3 ubiquitin ligase CHIP, thereby improving HSC71 stability. In HSC71-deficient or Crat-deficient crabs, hemocyte apoptosis was markedly enhanced, leading to higher host mortality upon S. eriocheiris challenge. Meanwhile, K579 acetylation on HSC71 weakened the interaction between HSC71 and superoxide dismutase (SOD), resulting in the accumulation of intracellular ROS and thereby restricting S. eriocheiris propagation. Pharmacological inhibition of the deacetylase SIRT1 with EX-527 enhanced HSC71 acetylation, elevated ROS production and reduced host susceptibility to S. eriocheiris infection in crabs. Notably, EX-527 similarly enhanced the acetylation of Drosophila melanogaster HSC71 homolog, HSPA8, which in turn impaired its interaction with SOD. This led to elevated ROS levels and restricted intracellular proliferation of S. eriocheiris in Drosophila S2 cells, demonstrating evolutionary conservation of this mechanism among arthropods. Therefore, this study established the modulation of HSC71 acetylation as a promising avenue to combat S. eriocheiris infection.