Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25

Abstract

Interleukin 17 (IL-17) plays an important role in infection and autoimmunity; how it signals remains poorly understood. In this study, we identified ubiquitin-specific protease 25 (USP25) as a negative regulator of IL-17-mediated signaling and inflammation. Overexpression of USP25 inhibited IL-17-triggered signaling, while USP25 deficiency resulted in increased phosphorylation of IκBα and Jnk, increased expression of chemokines and cytokines as well as prolonged half-life of Cxcl1 mRNA following IL-17 treatment. Consistently, Usp25-/- mice exhibited increased sensitivity to IL-17-dependent inflammation and autoimmunity in vivo. Mechanistically, IL-17 stimulation induced the association of USP25 with TRAF5 and TRAF6 and USP25 induced removal of Act1-mediated K63-linked ubiquitination in TRAF5 and TRAF6. Thus, our results demonstrate that USP25 is a deubiquitinating enzyme (DUB) that negatively regulates IL-17-triggered signaling.

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…Indeed, two deubiquitinating enzymes [DUB; the ubiquitin-specific protease USP25 and TNFAIP3 (also called A20)] were reported to be negative regulators of the IL-17-induced NF-kB cascade because they deubiquitinate TRAF6. 51,52 In addition, USP25 directly removes TRAF5 ubiquitination and consequently erases the signals for the TRAF5-dependent mRNA stabilization pathways. 51 More recently, a study showed that another DUB [MCPIP1 (also named Regnase-1)] served as a negative regulator of IL-17 signaling.…”

“…51,52 In addition, USP25 directly removes TRAF5 ubiquitination and consequently erases the signals for the TRAF5-dependent mRNA stabilization pathways. 51 More recently, a study showed that another DUB [MCPIP1 (also named Regnase-1)] served as a negative regulator of IL-17 signaling. 53 Unexpectedly, its endoribonuclease but not its deubiquitinase activity was required for the suppression of IL-17 signaling.…”

TRAF5-mediated Lys-63-linked Polyubiquitination Plays an Essential Role in Positive Regulation of RORγt in Promoting IL-17A Expression

“…The ubiquitin-specific protease USP18 plays a key role for T cells in the progres of differentiating into Th17 cells (5). USP25 could remove the Lys-63-linked ubiquitination in TRAF5 and TRAF6 mediated by Act1 and inhibit IL-17R signaling and inflammation (6).…”

Cutting Edge: Ubiquitin-Specific Protease 4 Promotes Th17 Cell Function under Inflammation by Deubiquitinating and Stabilizing RORγt

“…The proinflammatory cytokines TGF-b, IL-6, IL-1b, and IL-23 are essential to Th17 cell differentiation and function (1)(2)(3)(4). Several deubiquitinases (DUBs) or E3 ligases are important regulators of Th17 cell differentiation (5)(6)(7)(8). The orphan nuclear receptor RORgt is crucial for Th17 cell development, but the modulation of its stability remains uncharacterized (2,9).…”