MAFA Phosphorylation Controls Beta-Cell Identity and Sex-Specific Pancreatic Disease Outcomes

Abstract

Mafa is a critical transcription factor in pancreatic beta-cell biology, orchestrating insulin expression in response to glucose elevations. As a member of the large MAF protein family, MAFAs stability and activity are intricately regulated by GSK3-mediated phosphorylation. To decipher the functional roles of these phosphorylations, we engineered knock-in mice (Mafa4A/+) in which MAFA is rendered non-phosphorylatable. In all Mafa4A/+ animals, MAFA stability was markedly enhanced. Under high-fat diet (HFD) conditions, Mafa4A/+ males rapidly developed glucose intolerance, which was attributed to impaired glucose-stimulated insulin secretion. Bulk RNA sequencing revealed disrupted beta- cell identity, characterized by increased expression of MODY-associated genes and a delta-cell signature, suggesting beta-to-delta cell reprogramming, a hypothesis supported by lineage- tracing experiments. Conversely, Mafa4A/+ females exhibited hypoglycemia and, with age, developed pronounced inflammatory cystic ducts including mucinous cystic neoplasms (MCNs). Strikingly, MAFA protein was also detected in MCN biopsies from female patients, linking our findings to human pathology. Our results unveil a sex-biased impact of GSK3-mediated MAFA phosphorylation. The male phenotype closely parallels the MODY-like diabetes observed in patients with MAFA S64F mutations, implicating defective phosphorylation in disease etiology. The emergence of MCNs in female mice suggests a novel role for MAFA stability or mutations in the pathogenesis of these enigmatic neoplasms, providing a fresh molecular hypothesis with clinical relevance.