SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

Abstract

SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), is crucial in NF-κB signaling and inflammation. In this study, we revealed a LUBAC-independent function of SHARPIN in regulating melanoma growth. We found that SHARPIN interacts with PRMT5, a type II protein arginine methyltransferase, enhancing its multiprotein complex formation and methyltransferase activity. Activated PRMT5 modulates the expression of transcription factors SOX10 and MITF through SHARPIN-dependent arginine dimethylation and the inhibition of the transcriptional corepressor SKI. Additionally, SHARPIN’s activation of PRMT5 offsets its inhibition by methylthioadenosine, a substrate of methylthioadenosine phosphorylase, which is often co-deleted with cyclin-dependent kinase inhibitor 2A (CDKN2A) in about 15% of human cancers. Overall, we have identified a LUBAC-independent role for SHARPIN in promoting PRMT5 activity, which contributes to the development of GSK591 melanoma via the SKI/SOX10 regulatory pathway.