《生命科学》 2026, 38(1): 150-162
未折叠蛋白反应和泛素化修饰在免疫调节中的协同作用
摘 要：
内质网（endoplasmic reticulum，ER）在蛋白质合成、折叠和组装中发挥重要作用，其内部蛋白质产生受一组驻留机制紧密调节。在多种生理或病理条件下，未折叠蛋白或错误折叠蛋白在内质网腔蓄积引起内质网应激（endoplasmic reticulum stress，ERS），触发未折叠蛋白反应（unfolded protein response，UPR）以维持ER稳态。泛素化修饰是一种可逆的翻译后修饰，可调节蛋白质稳态。UPR和泛素化修饰均为细胞内重要的蛋白质质量控制机制，二者协同确保蛋白质生物合成的高准确度和高保真度，任一功能异常将导致蛋白质累积，进而加剧ERS，损伤细胞功能，引发疾病。本文首先概括了UPR和泛素化修饰的基本原理和功能，聚焦二者调控免疫细胞命运和维持免疫稳态等方面的协同作用，以期为寻找疾病诊疗相关的潜在靶点提供新视角。
通讯作者：刘 婉 , Email:liuwan@sdsmu.edu.cn 徐灵芝 , Email:xulz@sdsmu.edu.cn
Abstract:
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 systematically delineates the core principles of UPR signaling (via PERK, ATF6, and IRE1) and ubiquitination (via E1/E2/E3 enzymes), then examines their collaborative mechanisms across immune cell subsets. In innate immunity, dendritic cells (DCs) employ the HRD1-UBE2J1 ERAD (ER associated 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 Itchmediated 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 to ubiquitinate both misfolded FoxP3 and IRE1α, preventing excessive UPR and preserving suppressive function. CD4+ and CD8+ T cell activation is modulated by PERK-eIF2α inhibition of MHCI 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 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.
Communication Author：LIU Wan , Email:liuwan@sdsmu.edu.cn XU Ling-Zhi , Email:xulz@sdsmu.edu.cn
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