Journal of Biological Chemistry

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)P2, 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.

phosphatidylinositol transfer proteins

phosphoinositide

phosphoinositide kinases

PIPn-linked proteins

small heat shock proteins

Star-PAP

Bcl-2-interacting killer

branched polyethylenimine

liquid scintillation counting

microscale thermophoresis

phosphatidylinositol phosphates

phosphatidylinositol transfer protein

phosphatidylinositol 4,5-bisphosphate

phosphatidylinositol 4-monophosphate

phosphatidylinositol 3,4,5-trisphosphate

proximity ligation assay

small heat shock protein

speckle-targeted PIPKIα regulated-poly(A) polymerase

steroidogenic factor 1

© 2025 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biologyé