Palmitoylation of TRIM47 Regulates ATG16L1‐Mediated Autophagy to Exacerbate Respiratory Distress Syndrome in Sepsis

Acute respiratory distress syndrome (ARDS) is the deadliest complication of sepsis. Recent studies demonstrated that palmitoylation of proteins played an essential role in sepsis-induced tissue damage. This study investigated the function of TRIM47 palmitoylation in sepsis-induced ARDS. In vivo and in vitro models of sepsis-induced ARDS were induced by cecum ligation and puncture (CLP) and LPS, respectively. In vivo, lung injury was assessed by HE staining and autophagosome was observed by transmission electron microscopy. Meanwhile, LC3B intensity was detected using an immunofluorescence assay. Palmitoylation of TRIM47 was analyzed by ABE assay. Intermolecular interactions were verified by Co-IP. The palmitoylation of TRIM47 was increased and autophagy decreased in sepsis-induced ARDS in vivo and in vitro. Meanwhile, palmitoylation of TRIM47 at C520 inhibited autophagy to exacerbate sepsis-induced ARDS. Furthermore, knockdown of TRIM47 promoted ATG16L1 expression and palmitoylation of TRIM47 at C520 promoted ubiquitination of ATG16L1. Moreover, ZDHHC21 bound to TRIM47 and increased palmitoylation of TRIM47 to inhibit autophagy in sepsis-induced ARDS. In conclusion, this study demonstrated that ZDHHC21 mediated TRIM47 palmitoylation, thereby promoting ATG16L1 ubiquitination, leading to impaired autophagy, which exacerbated sepsis-induced ARDS.