Synergistic roles of unfolded protein responses and ubiquitination modifications in immunomodulation

This review aims to explore the intricate and synergistic interplay between the unfolded protein response (UPR) and ubiquitination modifications in regulating the immune system. Maintaining cellular protein homeostasis is fundamental for immune cell function, which often involves high rates of protein synthesis, folding, and degradation. Endoplasmic reticulum stress (ERS), caused by the accumulation of unfolded or misfolded proteins, triggers UPR to restore ER homeostasis. Simultaneously, ubiquitination, a reversible post-translational modification, precisely controls protein stability and degradation. Both mechanisms act as critical intracellular protein quality control systems, working in concert to ensure protein biosynthesis fidelity and proper immune function. Dysfunction in either pathway can lead to protein accumulation, exacerbating ERS and contributing to immune-related pathologies. The review <?A3B2 tlsb=-.03w?>systematically delineates the core principles of UPR signaling (via PERK, ATF6, and IRE1) and ubiquitination (via E1/E2/E3 <?A3B2 pi129?>enzymes), then examines their collaborative mechanisms across immune cell subsets. In innate immunity, dendritic cells (DCs) employ the HRD1-UBE2J1 ERAD (ER associated <?A3B2 tlsb?>degradation) complex to ubiquitinate misfolded MHC-I heavy chains, ensuring antigen presentation fidelity. Macrophages exhibit IFN-γ-induced STAT1/PIAS1-mediated ubiquitination of LXR-α, triggering PERK-CHOP-driven apoptosis and inflammation. NK cells utilize IL-15-PI3K/AKT signaling to suppress XBP1s ubiquitination, stabilizing this UPR transcription factor to enhance survival and granzyme B expression. In allergic responses, Cbl ligases ubiquitinate FcεRI and protein tyrosine kinases to attenuate UPR activation in basophils and mast cells. Conversely, in mast cell leukemia, valosin-containing protein (VCP) inhibitors disrupt ERAD, stabilizing oncogenic MTDH and perpetuating IRE1α-driven tumor survival. Intestinal innate lymphoid cells rely on IRE1α-XBP1s for cytokine production, a process restrained by Itch-mediated RORγt ubiquitination. In adaptive immunity, B cell development requires SEL1L-HRD1 ERAD-mediated degradation of pre-B cell receptors, while plasma cell differentiation depends on IRE1/XBP1-driven ER expansion for antibody secretion. Regulatory T cells employ HRD1 <?A3B2 pi129?>to ubiquitinate both misfolded FoxP3 <?A3B2 pi129?>and IRE1α, preventing excessive UPR and preserving suppressive function. CD4⁺ and CD8⁺ T cell activation is modulated by PERK-eIF2α inhibition of MHC-I synthesis and MARCH1-mediated MHC-II ubiquitination, collectively impairing antigen presentation in metabolic and immunodeficiency disorders. This analysis reveals that UPR-ubiquitination synergy orchestrates proteostasis, antigen presentation, survival, differentiation, and inflammation across innate and adaptive immunity. Therapeutically, targeting UPR kinases (IRE1α, PERK) or specific E3 <?A3B2 pi129?>ligases offers promise for cancer, autoimmunity, and allergy, with VCP inhibitors already showing efficacy in mast cell leukemia. Combination strategies simultaneously modulating both pathways may prevent compensatory activation and achieve superior clinical outcomes. This review provides a framework for precision immunotherapy by revealing how proteostasis networks shape immune function and disease.