USP4 interacts and positively regulates IRF8 function via K48‐linked deubiquitination in regulatory T cells

Abstract

CD4 CD25 regulatory T (Treg) cells comprise a unique subset of T cells required for maintaining immune homeostasis. However, the molecular mechanisms associated with the functional variety of Treg cells are not fully delineated. In the present study, we demonstrate that ubiquitin-specific protease (USP)4 physically interacted with interferon regulatory factor 8 (IRF8) function via a K48-linked deubiquitinase, which stabilized IRF8 protein levels in Treg cells. Depletion of USP4 promoted the polyubiquitination of IRF8 and the upregulation of type 2 inflammatory cytokine gene expression in Treg cells. Consistently, treatment of Treg cells with USP4 inhibitor facilitated the polyubiquitination of IRF8. In addition, the deficiency of USP4 alleviated the suppressive function of Treg cells. Taken together, our results suggest that USP4 interacts with and stabilizes IRF8 to promote the suppressive function of Treg cells.

IRF8: identity-keeper for suppressive Th1-like Treg cells

“…Two papers published recently support a role for IRF8 in Treg cell function. 19,20 In agreement with our own study, Lin et al showed that IRF8 is important for the suppressive function and identity of Treg cells. 19 Lin et al showed that ubiquitin-specific protease (USP) 4 interacts physically with IRF8 to promote K-48-linked deubiquitination, thereby stabilizing IRF8.…”

“…19,20 In agreement with our own study, Lin et al showed that IRF8 is important for the suppressive function and identity of Treg cells. 19 Lin et al showed that ubiquitin-specific protease (USP) 4 interacts physically with IRF8 to promote K-48-linked deubiquitination, thereby stabilizing IRF8. 19 shRNA-mediated knock-down of USP4 or its inhibition by Vialilin A reduces IRF8 protein levels and causes aberrantly high expression of Th2 (IL-4, IL-5, and IL-13) and Th17 (IL-21) cytokines in Treg cells; this causes Treg cells to lose suppressive function.…”

“…19 Lin et al showed that ubiquitin-specific protease (USP) 4 interacts physically with IRF8 to promote K-48-linked deubiquitination, thereby stabilizing IRF8. 19 shRNA-mediated knock-down of USP4 or its inhibition by Vialilin A reduces IRF8 protein levels and causes aberrantly high expression of Th2 (IL-4, IL-5, and IL-13) and Th17 (IL-21) cytokines in Treg cells; this causes Treg cells to lose suppressive function. 19 Carr et al showed that transcription factor JunB activates expression of Th17 lineagespecific genes and represses Th1 and Treg cells.…”

A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

“…For example, USP4 suppresses stress‐induced cell apoptosis and facilitates tumor metastasis in melanoma . USP4 promotes the suppressive function of Treg cells by interacting with and stabilizing interferon regulatory factor 8 (IRF8) . Furthermore, USP4 targets transforming growth factor‐β‐activated kinase 1 (TAK1) to regulate tumor necrosis factor‐α (TNFα)‐induced NF‐κB activation .…”

“…26 USP4 promotes the suppressive function of Treg cells by interacting with and stabilizing interferon regulatory factor 8 (IRF8). 27 Furthermore, USP4 targets transforming growth factor-β-activated kinase 1 (TAK1) to regulate tumor necrosis factor-α (TNFα)-induced NF-κB activation. 28 In HCC, USP4 facilitates tumor development via deubiquitylation and cyclophilin A stabilization.…”