Insulin post-transcriptional regulation via PARP12-mediated ADP- ribosylation

TL;DR

This study reveals how PARP12 modifies insulin mRNA, potentially reducing insulin production during type 1 diabetes development.

Contribution

The paper identifies PARP12 as a novel regulator of insulin mRNA through ADP-ribosylation during inflammation.

Findings

PARP12 expression increases in islets exposed to pro-inflammatory cytokines or in β cells from diabetic donors.

PARP12 ADP-ribosylates 150 mRNAs, including insulin mRNA, altering transcript localization and halting translation.

The RNA machinery in insulin-producing cells is regulated by PARP12 during inflammatory conditions.

Abstract

ADP-ribosylation is a common modification that occurs in proteins and nucleic acids, regulating many cellular processes ranging from DNA repair to inflammatory signaling. ADP-ribosylation plays an important role in cancer biology, infectious diseases, and obesity, but its role in the development of type 1 diabetes is not well understood. Here, we studied the role of ADP-ribosyltransferase PARP12 in type 1 diabetes development. PARP12 expression is highly induced in human islets treated with pro-inflammatory cytokines or β cells from diabetic donors. Proteomics analysis of MIN6 insulin-producing cells identified that the RNA machinery is regulated by PARP12 during inflammation. PARP12 also ADP-ribosylates 150 mRNAs, including the insulin mRNA. This mRNA ADP-ribosylation in turn modifies transcript localization and halts translation. Overall, our data identified a role for PARP12 in ADP-ribosylation and translation halting of mRNAs, which may affect insulin production during insulitis.