IRGQ-mediated autophagy in MHC class I quality control promotes tumor immune evasion

Affiliations

• Institute of Biochemistry II, Goethe University Frankfurt, Medical Faculty, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
• Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Institutes of Medicine, 450 Brookline Avenue, Boston, MA 02215, USA
• Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
• Institute of Biochemistry I, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
• Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany
• Max Planck Institute of Biophysics, Goethe University Frankfurt, Riedberg Campus, 60438 Frankfurt am Main, Germany
• Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
• Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands

PMID:  39481378  DOI: 10.1016/j.cell.2024.09.048

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.

自噬-溶酶体系统在降解多种细胞内物质方面发挥着重要作用，同时也与肿瘤进展有关。在这项研究中，我们发现免疫相关GTP酶家族Q蛋白（IRGQ）是一种尚未被充分研究的蛋白，它在主要组织相容性复合体I类（MHC class I）分子的质量控制中起着关键作用。IRGQ通过与GABARAPL2和LC3B结合，将错误折叠的MHC class I引导至溶酶体进行降解。在缺乏IRGQ的情况下，游离的MHC class I重链不仅在细胞内积累，还被转运到细胞表面，从而促进免疫反应。在患有肝细胞癌的小鼠和人类患者中，IRGQ水平降低的情况下，患者的生存率有所提高，这与CD8+ T细胞对IRGQ缺失肿瘤细胞的反应性增强有关。因此，我们揭示了IRGQ作为MHC class I质量控制的调节因子，其介导了肿瘤的免疫逃逸。

关键词：自噬，IRGQ，GABARAPL2，W6/32，HLA，MHC，佰乐博，佰乐博生物