Ubiquitin-specific proteases: Key regulators in TLR/IL-1R signaling and inflammatory disease progression

Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs) initiate a myriad of overlapping inflammatory responses through their shared Toll/IL-1 receptor (TIR) domains, which recruit adaptor proteins and eventually converge signaling on TRAF6 for downstream activation. This cascade heavily relies on ubiquitination, which determines the strength and duration of these signals, highlighting the critical roles of E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) in orchestrating immune responses mediated by these receptor families. While TRAF6 is well recognized as an E3 ligase that catalyzes lysine-63 (K63) polyubiquitination to activate downstream NF‑κB and MAPK pathways, increasing attention has focused on the counteracting roles of DUBs, particularly ubiquitin-specific proteases (USPs) that remove ubiquitin chains from TRAF6 and other signaling nodes. Accumulating evidence reveals that USPs function as either negative or positive regulators of TRAF6 signaling, and their dysregulation is linked to diverse inflammatory diseases. In this review, we first outline the pivotal role of TRAF6‑mediated ubiquitination in TLR/IL‑1 R pathways. We then systematically categorize USPs that regulate TRAF6 signaling, either by directly deubiquitinating TRAF6 or by acting indirectly. We also highlight how USPs shape inflammatory outcomes through mechanisms independent of TRAF6 in diverse inflammation‑driven disorders, including allergic airway disease, cardiovascular disease, metabolic syndrome, and neuropathic pain. By integrating molecular mechanisms with disease contexts, we provide a framework for understanding USP functions and their therapeutic potential in inflammation‑driven diseases.