聚腺苷酸聚合酶Star-PAP受稳定结合的磷酸肌醇信使调控。

The poly(A) polymerase Star-PAP is regulated by stably associated phosphoinositide messengers.

作者信息

Wen Tianmu, Chen Mo, Cryns Vincent L, Anderson Richard A

机构信息

University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA.

University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA; Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China.

出版信息

J Biol Chem. 2025 Jun 24;301(8):110412. doi: 10.1016/j.jbc.2025.110412.

DOI:10.1016/j.jbc.2025.110412

PMID:40570960

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12284501/

Abstract

Star-PAP is a noncanonical poly(A) polymerase that controls gene expression. Star-PAP was previously reported to bind PIPKI⍺ and its product PI(4,5)P, which regulate Star-PAP activity and expression of specific genes. Recent studies have revealed a nuclear p53-phosphoinositide signaling pathway in which the phosphatidylinositol transfer proteins (PITPs) and phosphoinositide kinases/phosphatases bind p53 to sequentially modify p53-linked phosphoinositides and regulate p53 function. Here, we demonstrate that multiple phosphoinositides are also coupled to Star-PAP in response to stress. This pathway is initiated by PITP⍺/β binding to Star-PAP, and the Star-PAP-phosphoinositide complexes are sequentially modified by PI4KII⍺, PIPKI⍺, IPMK, and PTEN. The formation of Star-PAP-phosphoinositide complexes enhances the association of the small heat shock proteins HSP27 and ⍺B-crystallin with Star-PAP. Knockdown of the PITPs, PIP kinases, or HSP27 reduces the expression of Star-PAP targets. Our results demonstrate that PITP⍺/β play a key role in the assembly of Star-PAP-phosphoinositide complexes that are sequentially interconverted by PIP kinases/phosphatases and recruit the small heat shock proteins to these complexes to regulate Star-PAP activity in response to stress.

摘要

Star-PAP是一种控制基因表达的非典型多聚腺苷酸聚合酶。此前有报道称，Star-PAP可与PIPKIα及其产物PI(4,5)P结合，它们可调节Star-PAP活性及特定基因的表达。最近的研究揭示了一条细胞核p53-磷酸肌醇信号通路，其中磷脂酰肌醇转移蛋白（PITPs）和磷酸肌醇激酶/磷酸酶与p53结合，依次修饰与p53相连的磷酸肌醇并调节p53功能。在此，我们证明在应激反应中多种磷酸肌醇也与Star-PAP偶联。该信号通路由PITPα/β与Star-PAP结合启动，Star-PAP-磷酸肌醇复合物依次被PI4KIIα、PIPKIα、IPMK和PTEN修饰。Star-PAP-磷酸肌醇复合物的形成增强了小热休克蛋白HSP27和αB-晶状体蛋白与Star-PAP的结合。敲低PITPs、PIP激酶或HSP27会降低Star-PAP靶标的表达。我们的结果表明，PITPα/β在Star-PAP-磷酸肌醇复合物的组装中起关键作用，这些复合物由PIP激酶/磷酸酶依次相互转化，并招募小热休克蛋白至这些复合物，以在应激反应中调节Star-PAP活性。