Protein Inhibitor of Activated STAT Y (PIASy) Regulates Insulin Secretion by Interacting with LIM Homeodomain Transcription Factor Isl1.

Chengzhi Yan,Yan Cui,Chulin Yu,Di Zhang,Sheng Cui,Jinlian Zhou

doi:10.1038/srep39308

Abstract

It is known that the LIM homeodomain transcription factor Isl1 is highly expressed in all pancreatic endocrine cells and functions in regulating pancreatic development and insulin secretion. The Isl1 mutation has been found to be associated with type 2 diabetes, but the mechanism responsible for Isl1 regulation of insulin synthesis and secretion still needs to be elucidated. In the present study, the protein inhibitor of activated STAT Y (PIASy) was identified as a novel Isl1-interacting protein with a yeast two-hybrid system, and its interaction with Isl1 was further confirmed by a co-immunoprecipitation experiment. PIASy and Isl1 colocalize in human and mouse pancreas and NIT beta cells. Furthermore, PIASy and Isl1 upregulate insulin gene expression and insulin secretion in a dose-dependent manner by activating the insulin promoter. PIASy and Isl1 mRNA expression levels were also increased in type 2 diabetic db/db mice. In addition, our results demonstrate that PIASy and Isl1 cooperate to activate the insulin promoter through the Isl1 homeodomain and PIASy ring domain. These data suggest that that PIASy regulates insulin synthesis and secretion by interacting with Isl1 and provide new insight into insulin regulation, although the detailed molecular mechanism needs to be clarified in future studies.

Highlights

Protein inhibitors of activated STAT (PIAS) family proteins were originally found through their interaction with the signal transducer and activator of transcription (STAT) family of transcription factors[16]
Our results presented here demonstrate that protein inhibitor of activated STAT Y (PIASy) is a novel factor that regulates insulin transcriptional activity and secretion by interacting with Isl[1] in a synergistic manner and that the homeodomain of Isl[1] and the ring domain of PIASy are required for the coactivation of the insulin promoter
The interaction between full-length or deleted Isl[1] and PIASy was further confirmed on DDO/ X/A medium (Fig. 1b) and higher stringency QDO/X/A medium (Fig. 1c). These results indicated that PIASy is a novel Isl1-interacting protein

Summary

Introduction

Protein inhibitors of activated STAT (PIAS) family proteins were originally found through their interaction with the signal transducer and activator of transcription (STAT) family of transcription factors[16]. Our results presented here demonstrate that PIASy is a novel factor that regulates insulin transcriptional activity and secretion by interacting with Isl[1] in a synergistic manner and that the homeodomain of Isl[1] and the ring domain of PIASy are required for the coactivation of the insulin promoter. These findings contribute to our understanding of the mechanism regulating insulin secretion

Methods

Results

Conclusion