IgIT2-SHP2 axis inhibits the autophagy through P38-H3K4me3 pathway in oyster Crassostrea gigas.

Inhibitory receptors containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) are generally known to suppress the activation of immune cells through the recruitment of protein tyrosine phosphatase, such as SHP-1/2, SHIP1/2. In our previous study, the inhibitory receptor CgIgIT2 was identified from Crassostrea gigas, and it was composed of four immunoglobulin (Ig) domains, a single fibronectin type III (FN3) domain, a transmembrane region, and a cytoplasmic tail with two ITIM motifs and one immunoreceptor tyrosine-based switch motif (ITSM). Among which, the Ig domains had binding activities to various pathogen-associated molecular patterns (PAMPs) and microbes. In the present study, the recombinant FN3 domain of CgIgIT2 also exhibited binding activities towards various PAMPs and microbes. Upon binding microbes, CgIgIT2 was activated and recruited CgSHP2 to inhibit the phosphorylation levels of CgP38. The inhibition of CgP38 reduced the histone H3 lysine 4 trimethylation (H3K4me3), which eventually reduced the mRNA expression levels of autophagy related factors (CgATG5, CgLC3, and CgOPTN) and the rate of hemocyte autophagy. These results suggested that IgIT2-SHP2 axis upon binding different PAMPs and microbes inhibited CgP38 activation to reduce CgH3K4me3 level, leading to the suppression of autophagy.