Work

The peptidyl‐prolyl cis‐trans isomerase, Pin1, is a regulator of the protein kinase C θ ( PKCθ ) catalytic activity in activated T cells

Year: 2025

Type: article

Abstract: Protein kinase C θ (PKCθ) is expressed in T lymphocytes, in which it plays a crucial role in cell activation, proliferation, and differentiation. Previously, we discovered that the Thr 335 ‐Pro motif within the PKCθ‐V3 regulatory domain serves as a critical site for PKCθ activation and demonstrated that phosphorylation of the Thr 335 ‐Pro motif creates a binding site for the peptidyl‐prolyl cis‐trans isomerase (PPIase), Pin1. Herein, we elaborate on the functional consequences of the Pin1‐PKCθ association and identify Pin1 as a regulator of PKCθ catalytic activity. Pin1 downregulated the activity of PKCθ in vitro in PMA‐stimulated human Jurkat T cells and C57BL/6J mouse spleen‐ and thymus‐derived T lymphocytes, an effect that was reversed by juglone, a Pin1‐activity inhibitor. Utilizing Pin1 isomerase‐deficient mutants, we demonstrate that the functionality of the Pin1 catalytic domain is essential for its regulation of PKCθ, suggesting that Pin1 mediates its inhibitory effect on PKCθ via cis‐trans isomerization. In silico docking analysis supported the role of critical residues within the Pin1‐PPIase domain that enables the cis‐trans interconversion of the PKCθ phospho‐Thr 335 ‐Pro motif. Retroviral knockdown of Pin1 in Jurkat T cells led to an elevation in PKCθ kinase activity. Furthermore, stimulation of [Lck cre × Pin1 lox ] F 1 mice‐derived Pin1‐deficient T cells augmented the phosphorylation of SPAK kinase, a bona fide PKCθ downstream substrate. Together, our results support a role for the Pin1 isomerase as a regulator of PKCθ activity and highlight the potential contribution of Pin1 to the fine‐tuning of the T cell activation dynamics.

Source: Protein Science

DOI: 10.1002/pro.70414