One protein, many faces: TRAF1 from signaling hub to disease diversity

Abstract

Tumor necrosis factor receptor-associated factor 1 (TRAF1) is a unique member of the TRAF family, distinguished by its lack of an N-terminal RING domain. At the transcriptional level, TRAF1 expression is regulated by diverse mechanisms, including methylation, RNA-binding domain (RBD) proteins, and microRNAs. Post-translationally, TRAF1 undergoes modifications such as M1-linked ubiquitination and phosphorylation. In immune signaling pathways, TRAF1 usually displays functional duality: it activates the canonical NF-κB pathway by enhancing cIAP recruitment downstream of TNFR1, whereas at death domain-lacking TNFR superfamily members (NDDTNFRs), it drives the non-canonical NF-κB pathway through TRAF3 degradation. Conversely, TRAF1 often acts as a negative regulator in Toll-like receptor (TLR) signaling. Within the MAPK pathway, TRAF1 participates in modulating multiple cascades, including ASK1/B-Raf(BRAF)/ERK1. In immune-mediated diseases, TRAF1 contributes to disease pathogenesis by regulating inflammatory cytokines, matrix metalloproteinase (MMP) expression, synovial cell apoptosis and tissue destruction. In infectious diseases, the anti-apoptotic effect of TRAF1 downstream of the 4-1BB signaling pathway serves as a host strategy to combat viral infections by preserving CD8+ T cell survival. However, Helicobacter pylori exploits TRAF1 upregulation to inhibit apoptosis in gastric epithelial cells, facilitating its persistent colonization. This contrast highlights TRAF1's functional diversity across infections. This review summarizes the post-translational regulation of TRAF1, its dual roles in signaling pathways, and its contributions to immune-related and infectious diseases, aiming to clarify its mechanistic complexity within the existing biological framework.