HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease PMID: 32647003

ADC Targets in Oncology

2026-04-10

HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease

Science. 2020 Jul 10;369(6500):202-207. doi: 10.1126/science.aay5663.

Sarah A Cook ^# ¹ , William A Comrie ^# ¹ ² , M Cecilia Poli ³ ⁴ ⁵ , Morgan Similuk ⁶ , Andrew J Oler ⁷ , Aiman J Faruqi ¹ , Douglas B Kuhns ⁸ , Sheng Yang ⁹ , Alexander Vargas-Hernández ³ ⁴ , Alexandre F Carisey ³ ⁴ , Benjamin Fournier ¹⁰ ¹¹ , D Eric Anderson ¹² , Susan Price ¹³ , Margery Smelkinson ¹⁴ , Wadih Abou Chahla ¹⁵ , Lisa R Forbes ³ ⁴ , Emily M Mace ¹⁶ , Tram N Cao ³ ⁴ , Zeynep H Coban-Akdemir ¹⁷ ¹⁸ , Shalini N Jhangiani ¹⁸ ¹⁹ , Donna M Muzny ¹⁸ ¹⁹ , Richard A Gibbs ¹⁷ ¹⁸ ¹⁹ , James R Lupski ¹⁷ ¹⁸ ¹⁹ , Jordan S Orange ¹⁶ , Geoffrey D E Cuvelier ²⁰ , Moza Al Hassani ²¹ , Nawal Al Kaabi ²¹ , Zain Al Yafei ²¹ , Soma Jyonouchi ²² ²³ , Nikita Raje ²⁴ ²⁵ , Jason W Caldwell ²⁶ , Yanping Huang ²⁷ ²⁸ , Janis K Burkhardt ²⁷ , Sylvain Latour ¹⁰ ¹¹ , Baoyu Chen ⁹ , Gehad ElGhazali ²¹ , V Koneti Rao ¹³ , Ivan K Chinn ³ ⁴ , Michael J Lenardo ²⁹

Affiliations

1. Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
2. Neomics Pharmaceuticals, LLC, Gaithersburg, MD, USA.
3. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
4. Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children's Hospital, Houston, TX, USA.
5. Program of Immunogenetics and Translational Immunology, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile.
6. Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
7. Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD, USA.
8. Neutrophil Monitoring Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
9. Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, USA.
10. Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR 1163, Paris, France.
11. University Paris Descartes Sorbonne Paris Cité, Institut des Maladies Génétiques-IMAGINE, Paris, France.
12. Advanced Mass Spectrometry Facility, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA.
13. Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.
14. Biological Imaging Section, Research Technologies Branch, NIAID, NIH, Bethesda, MD, USA.
15. Department of Pediatric Hematology, Jeanne de Flandre Hospital, Centre Hospitalier Universitaire (CHU), Lille, France.
16. Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
17. Baylor-Hopkins Center for Mendelian Genomics, Houston, TX, USA.
18. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
19. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
20. Section of Pediatric Hematology/Oncology/BMT, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.
21. Sheikh Khalifa Medical City, Abu Dhabi Healthcare Company (SEHA), Abu Dhabi, United Arab Emirates.
22. Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
23. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
24. Division of Allergy, Immunology, Pulmonary, and Sleep Medicine, Children's Mercy Hospital, Kansas City, MO, USA.
25. Department of Internal Medicine and Pediatrics, University of Missouri Kansas City, Kansas City, MO, USA.
26. Section of Pulmonary, Critical Care, Allergy and Immunological Diseases, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
27. Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
28. Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
29. Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. [email protected].
# Contributed equally.

Abstract

Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in NCKAP1L, which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent Akt phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.