Otto Meyerhof Prize
IRGQ-Mediated Autophagy in MHC-I Quality Control Drives Tumor Immune Evasion

Lina Herhaus^1,9,10*, Uxía Gestal-Mato^1,9, Vinay V. Eapen^2,3, Igor Mačinković^1,4, Henry J. Bailey^1,5, Cristian Prieto-Garcia¹, Mohit Misra^1,5, Anne-Claire Jacomin¹, Aparna Viswanathan Ammanath¹, Ivan Bagarić¹, Jolina Michaelis¹, Joshua Vollrath^1,5,6, Ramachandra M. Bhaskara^1,5, Georg Bündgen⁷, Adriana Covarrubias-Pinto¹, Koraljka Husnjak¹, Jonathan Zöller⁶, Ajami Gikandi², Sara Ribičić¹, Tobias Bopp⁷, Gerbrand J. van der Heden van Noort⁸, Julian D. Langer⁶, Andreas Weigert⁴, J. Wade Harper³, Joseph D. Mancias², Ivan Dikic ^1,5,6,*

1 Institute of Biochemistry II, Goethe University Frankfurt, Medical Faculty, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
2 Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Institutes of Medicine, 450 Brookline Avenue, Boston, MA 02215
3 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115
4 Institute of Biochemistry I, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
5 Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany
6 Max Planck Institute of Biophysics, Goethe University Frankfurt, Riedberg Campus, 60438 Frankfurt am Main, Germany
7 Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
8 Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
9 These authors contributed equally
10 current address: HZI - Helmholtz Centre for Infection Research, Cellular Immune Signals, Inhoffenstraße 7, 38124 Braunschweig, Germany
*Shared senior authorship, correspondence should be addressed to: dikic@biochem2.uni-frankfurt.de; lina.herhaus@gmail.com

The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here we show that immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of MHC-I molecules. IRGQ directs misfolded MHC-I towards lysosomal degradation through its unique binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC-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 towards IRGQ knock-out tumor cells. Thus, we reveal IRGQ as a novel regulator of MHC-I quality control, mediating tumor immune evasion.

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