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

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.