2. Academic Validation
  3. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease

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

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. lenardo@nih.gov.
  • # Contributed equally.
PMID: 32647003 DOI: 10.1126/science.aay5663
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.

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