GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans

Yikun Yao; Ping Du Jiang; Brittany N Chao; Deniz Cagdas; Satoshi Kubo; Arasu Balasubramaniyam; Yu Zhang; Bella Shadur; Adeeb NaserEddin; Les R Folio; Benjamin Schwarz; Eric Bohrnsen; Lixin Zheng; Matthew Lynberg; Simone Gottlieb; Michael A Leney-Greene; Ann Y Park; Ilhan Tezcan; Ali Akdogan; Rahsan Gocmen; Sevgen Onder; Avi Rosenberg; Elizabeth J Soilleux; Errin Johnson; Peter K Jackson; Janos Demeter; Samuel D Chauvin; Florian Paul; Matthias Selbach; Haydar Bulut; Menna R Clatworthy; Zewen K Tuong; Hanlin Zhang; Benjamin J Stewart; Catharine M Bosio; Polina Stepensky; Simon Clare; Sundar Ganesan; John C Pascall; Oliver Daumke; Geoffrey W Butcher; Andrew J McMichael; Anna Katharina Simon; Michael J Lenardo

doi:10.1084/jem.20201405

GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans

J Exp Med. 2022 Jun 6;219(6):e20201405. doi: 10.1084/jem.20201405. Epub 2022 May 13.

Authors

Yikun Yao^#^{1

2}, Ping Du Jiang^#^{1

2}, Brittany N Chao^#^{1

2

3

4}, Deniz Cagdas^#^{5

6

7}, Satoshi Kubo^{1

2}, Arasu Balasubramaniyam^{8

9}, Yu Zhang¹⁰, Bella Shadur^{11

12

13}, Adeeb NaserEddin¹¹, Les R Folio¹⁴, Benjamin Schwarz¹⁵, Eric Bohrnsen¹⁵, Lixin Zheng^{1

2}, Matthew Lynberg^{1

2}, Simone Gottlieb^{1

2}, Michael A Leney-Greene^{1

10}, Ann Y Park^{1

2}, Ilhan Tezcan^{5

6

7}, Ali Akdogan¹⁶, Rahsan Gocmen¹⁷, Sevgen Onder¹⁸, Avi Rosenberg^{19

20}, Elizabeth J Soilleux²¹, Errin Johnson²², Peter K Jackson²³, Janos Demeter²³, Samuel D Chauvin^{1

2}, Florian Paul⁸, Matthias Selbach^{8

24}, Haydar Bulut^{8

9}, Menna R Clatworthy^{25

26}, Zewen K Tuong^{25

26}, Hanlin Zhang⁴, Benjamin J Stewart^{25

26}, Catharine M Bosio¹⁵, Polina Stepensky¹¹, Simon Clare²⁷, Sundar Ganesan²⁸, John C Pascall²⁹, Oliver Daumke^{8

9}, Geoffrey W Butcher²⁹, Andrew J McMichael^#³, Anna Katharina Simon^#⁴, Michael J Lenardo^#^{1

2}

Affiliations

¹ Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
² National Institute of Allergy and Infectious Diseases Clinical Genomics Program, Rockville, MD.
³ Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁴ Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, UK.
⁵ Division of Immunology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
⁶ Department of Pediatric Immunology, Institute of Child Health, Hacettepe University, Ankara, Turkey.
⁷ Ihsan Dogramaci Childrens Hospital, Hacettepe University Faculty of Medicine, Ankara, Turkey.
⁸ Crystallography, Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
⁹ Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 6, Berlin, Germany.
¹⁰ Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Rockville, MD.
¹¹ Hadassah University Medical Center, Department of Bone Marrow Transplantation and Cancer Immunotherapy, Jerusalem, Israel.
¹² The Garvan Institute of Medical Research, Immunology Division, Darlinghurst, Sydney, Australia.
¹³ St Vincent's Clinical School, University of New South Wales, Darlinghurst, Sydney, Australia.
¹⁴ Clinical Center, National Institutes of Health, Bethesda, MD.
¹⁵ Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, Rockville, MD.
¹⁶ Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey.
¹⁷ Department of Radiology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
¹⁸ Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
¹⁹ Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
²⁰ Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD.
²¹ Department of Pathology, University of Cambridge, Cambridge, UK.
²² The Dunn School of Pathology, South Parks Road, Oxford, UK.
²³ Baxter Laboratory, Departments of Microbiology & Immunology and Pathology Stanford University School of Medicine, Stanford, CA.
²⁴ Charité Universitätsmedizin Berlin, Berlin, Germany.
²⁵ Molecular Immunity Unit, University of Cambridge Department of Medicine, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
²⁶ Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK.
²⁷ Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK.
²⁸ Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, Rockville, MD.
²⁹ Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Babraham Research Campus, Cambridge, UK.

^# Contributed equally.

Abstract

Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6-/- mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipids. We find that GIMAP6 complexes with GABARAPL2 and GIMAP7 to regulate GTPase activity. Also, GIMAP6 is induced by IFN-γ and plays a critical role in antibacterial immunity. Finally, we observed that Gimap6-/- mice died prematurely from microangiopathic glomerulosclerosis most likely due to GIMAP6 deficiency in kidney endothelial cells.

This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural

MeSH terms

Animals
Autophagy
Endothelial Cells / metabolism
GTP Phosphohydrolases* / genetics
GTP Phosphohydrolases* / metabolism
Humans
Immunologic Deficiency Syndromes*
Inflammation
Mice

Substances

GIMAP6 protein, human
GTP Phosphohydrolases

Abstract

Publication types

MeSH terms

Substances

Grants and funding