Palmitoyltransferase ZDHHC3 Aggravates Nonalcoholic Steatohepatitis by Targeting S‐Palmitoylated IRHOM2 (Adv. Sci. 28/2023)

ZDHHC3 In article number 2302130, Minxuan Xu, Jun Tan, Benkui Zou, Bochu Wang, and co‐workers identify ZDHHC3 as a novel and critical acetyltransferase required for the IRHOM2 palmitoylation. Metabolic stresses‐triggered increase of ZDHHC3 maintains palmitoylated IRHOM2 accumulation by blocking its ubiquitination, consequently suppressing its ubiquitin‐proteasome‐related degradation mediated by TRIM31. Hepatocyte‐specific dysfunction of ZDHHC3 significantly inhibits palmitoylated IRHOM2 deposition, therefore suppressing the hepatosteatosis and inflammation in NASH pathological phenotype. This work uncovers that ZDHHC3‐induced palmitoylation is a novel regulatory mechanism and signal that regulate IRHOM2 trafficking‐related NASH progression. [Image: see text]