VCPIP1 potentiates innate immune responses by non-catalytically reducing the ubiquitination of IRAK1/2

Liyan Lou; Jiangyun Shen; Jianzhao Zhang; Fuqi Mei; Deyu Deng; Deqi Wang; Yanqi Xu; Kangmin Chen; Baoli Cheng; Jinghua Liu; Xu Wang

doi:10.1016/j.celrep.2025.115931

VCPIP1 potentiates innate immune responses by non-catalytically reducing the ubiquitination of IRAK1/2

Cell Rep. 2025 Jun 27;44(7):115931. doi: 10.1016/j.celrep.2025.115931. Online ahead of print.

Authors

Liyan Lou¹, Jiangyun Shen¹, Jianzhao Zhang¹, Fuqi Mei¹, Deyu Deng¹, Deqi Wang², Yanqi Xu¹, Kangmin Chen¹, Baoli Cheng³, Jinghua Liu⁴, Xu Wang⁵

Affiliations

¹ School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou 325000, China.
² The First School of Medicine and School of Information and Engineering, Wenzhou Medical University, Wenzhou 325035, China.
³ Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
⁴ Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
⁵ School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou 325000, China. Electronic address: sunrim@163.com.

PMID: 40581931
DOI: 10.1016/j.celrep.2025.115931

Abstract

The host innate immune system is efficiently activated after recognizing microbial components, such as lipopolysaccharide (LPS), by Toll-like receptors (TLRs). However, the molecular basis for the regulation of TLR-mediated signaling remains poorly understood. Here, we report that valosin containing protein interacting protein 1 (VCPIP1), a deubiquitinating enzyme, acts as a critical positive regulator of TLR4 signaling. TLR4 activation induces the upregulation and nuclear-to-cytoplasmic translocation of VCPIP1. The cytoplasmic VCPIP1 interacts with interleukin-1 receptor-associated kinase 1 and 2 (IRAK1/2) and maintains IRAK1/2 protein levels by reducing their degradation through the ubiquitin-proteasome system. Instead of directly deubiquitinating IRAK1/2 through the enzymatic activity, VCPIP1 blocks the K48 ubiquitination of IRAK1/2 in a non-catalytic manner. Ablation of VCPIP1 significantly attenuates LPS-induced inflammatory gene expression in macrophages. Consistently, VCPIP1-deficient mice are less susceptible to sepsis. Thus, this work reveals an essential role of VCPIP1 in TLR4 signaling and suggests that VCPIP1 may become a potential therapeutic target for inflammatory diseases.

Keywords: CP: Cell biology; CP: Immunology; VCPIP1; innate immune response; sepsis; signal transduction; ubiquitination.