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Intestinal ischemia–reperfusion (I/R) is a common clinical problem that occurs during various clinical pathological processes. Excessive apoptosis has an indispensable role in intestinal I/R injury. Tumor necrosis factor receptor-associated factor 2 (TRAF2) and PKC ζ  have an essential role in apoptosis. Here, we aimed to investigate the effects of PKC ζ  and TRAF2 and to explore the correlation between PKC ζ  and TRAF2 in intestinal I/R injury. Mice were subjected to intestinal I/R injury  in vivo .  In vitro  experiments were conducted by treating Caco-2 cells with hypoxia/reoxygenation (H/R) stimulation to simulate intestinal I/R. Intestinal tissue samples and Caco-2 cells were examined using various approaches. Intestinal I/R induced the membrane translocation and phosphorylation of PKC ζ . Pretreatment with the PKC ζ  activator phosphatidylcholine remarkably attenuated gut injury by suppressing apoptosis. H/R induced PKC ζ  to combine with TRAF2, which was phosphorylated by PKC ζ  at Ser 55 , but not at Ser 11 , under intestinal I/R or H/R conditions. In addition, TRAF2 Ser 55  phosphorylation increased cell survival by inhibiting cell apoptosis in the H/R model. Mechanistically, TRAF2 Ser 55  phosphorylation promoted NF- κ B activation but suppressed c-Jun activation in Caco-2 cells under H/R conditions. The results of this study demonstrate that the PKC ζ /TRAF2 pathway represents a novel protective mechanism against intestinal I/R injury. Therefore, the PKC ζ /TRAF2 pathway is a novel target for potential treatments of intestinal I/R injury-related diseases.

PKCζ phosphorylates TRAF2 to protect against intestinal ischemia–reperfusion–induced injury