Abstract
The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here, we show that the immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of major histocompatibility complex class I (MHC class I) molecules. IRGQ directs misfolded MHC class I toward lysosomal degradation through its binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC class I heavy chains do not only accumulate in the cell but are also transported to the cell surface, thereby promoting an immune response. Mice and human patients suffering from hepatocellular carcinoma show improved survival rates with reduced IRGQ levels due to increased reactivity of CD8+ T cells toward IRGQ knockout tumor cells. Thus, we reveal IRGQ as a regulator of MHC class I quality control, mediating tumor immune evasion.
摘要
自噬-溶酶体系统引导着多种货物的降解，也参与了肿瘤的进展。在这里，我们发现免疫相关GTPase家族Q蛋白（IRGQ）--一种迄今为止尚未定性的蛋白质--参与了主要组织相容性复合体I类（MHC I类）分子的质量控制。IRGQ通过其与GABARAPL2和LC3B的结合模式将折叠错误的MHC I类导向溶酶体降解。在缺乏IRGQ的情况下，游离的MHC I类重链不仅会在细胞内积聚，还会被运输到细胞表面，从而促进免疫反应。由于CD8+ T细胞对IRGQ基因敲除肿瘤细胞的反应性增加，小鼠和人类肝细胞癌患者在IRGQ水平降低的情况下生存率有所提高。因此，我们揭示了IRGQ是MHC I类质量控制的调节因子，可介导肿瘤免疫逃避。
原文链接
Herhaus L, Gestal-Mato U, Eapen VV,
Mačinković I, Bailey HJ, Prieto-Garcia C, Misra M, Jacomin AC, Ammanath
AV, Bagarić I, Michaelis J, Vollrath J, Bhaskara RM, Bündgen G,
Covarrubias-Pinto A, Husnjak K, Zöller J, Gikandi A, Ribičić S, Bopp T,
van der Heden van Noort GJ, Langer JD, Weigert A, Harper JW, Mancias JD,
Dikic I. IRGQ-mediated autophagy in MHC class I quality control
promotes tumor immune evasion. Cell. 2024 Oct 21:S0092-8674(24)01148-6.
doi: 10.1016/j.cell.2024.09.048. Epub ahead of print. PMID: 39481378.
