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

  1. Author:
    Cook, Sarah A [ORCID]
    Comrie, William A [ORCID]
    Poli, M Cecilia [ORCID]
    Similuk, Morgan [ORCID]
    Oler, Andrew J [ORCID]
    Faruqi, Aiman J [ORCID]
    Kuhns,Doug [ORCID]
    Yang, Sheng [ORCID]
    Vargas-Hernández, Alexander
    Carisey, Alexandre F [ORCID]
    Fournier, Benjamin [ORCID]
    Anderson, D Eric [ORCID]
    Price, Susan [ORCID]
    Smelkinson, Margery [ORCID]
    Abou Chahla, Wadih [ORCID]
    Forbes, Lisa R [ORCID]
    Mace, Emily M [ORCID]
    Cao, Tram N
    Coban-Akdemir, Zeynep H [ORCID]
    Jhangiani, Shalini N [ORCID]
    Muzny, Donna M [ORCID]
    Gibbs, Richard A [ORCID]
    Lupski, James R [ORCID]
    Orange, Jordan S [ORCID]
    Cuvelier, Geoffrey D E [ORCID]
    Al Hassani, Moza
    Al Kaabi, Nawal
    Al Yafei, Zain
    Jyonouchi, Soma
    Raje, Nikita
    Caldwell, Jason W [ORCID]
    Huang, Yanping
    Burkhardt, Janis K [ORCID]
    Latour, Sylvain [ORCID]
    Chen, Baoyu [ORCID]
    ElGhazali, Gehad
    Rao, V Koneti [ORCID]
    Chinn, Ivan K [ORCID]
    Lenardo, Michael J [ORCID]

  2. Author Address

    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., Neomics Pharmaceuticals, LLC, Gaithersburg, MD, USA., Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children 39;s Hospital, Houston, TX, USA., Program of Immunogenetics and Translational Immunology, Instituto de Ciencias e Innovaci 243;n en Medicina, Facultad de Medicina, Cl 237;nica Alemana-Universidad del Desarrollo, Santiago, Chile., Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA., Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD, USA., Neutrophil Monitoring Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, USA., Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR 1163, Paris, France., University Paris Descartes Sorbonne Paris Cit 233;, Institut des Maladies G 233;n 233;tiques-IMAGINE, Paris, France., Advanced Mass Spectrometry Facility, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA., Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA., Biological Imaging Section, Research Technologies Branch, NIAID, NIH, Bethesda, MD, USA., Department of Pediatric Hematology, Jeanne de Flandre Hospital, Centre Hospitalier Universitaire (CHU), Lille, France., Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA., Baylor-Hopkins Center for Mendelian Genomics, Houston, TX, USA., Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA., Section of Pediatric Hematology/Oncology/BMT, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada., Sheikh Khalifa Medical City, Abu Dhabi Healthcare Company (SEHA), Abu Dhabi, United Arab Emirates., Division of Allergy and Immunology, Children 39;s Hospital of Philadelphia, Philadelphia, PA, USA., Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Division of Allergy, Immunology, Pulmonary, and Sleep Medicine, Children 39;s Mercy Hospital, Kansas City, MO, USA., Department of Internal Medicine and Pediatrics, University of Missouri Kansas City, Kansas City, MO, USA., Section of Pulmonary, Critical Care, Allergy and Immunological Diseases, Wake Forest University School of Medicine, Winston-Salem, NC, USA., Department of Pathology and Laboratory Medicine, Children 39;s Hospital of Philadelphia Research Institute and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA., 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.,
    1. Year: 2020
    2. Date: Jul 10
  2. Journal: Science (New York, N.Y.)
    1. 369
    2. 6500
    3. Pages: 202-207
  4. Type of Article: Article
  5. ISSN: 0036-8075
  1. 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. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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External Sources

  1. View Full Text
  2. DOI: 10.1126/science.aay5663
  3. PMID: 32647003
  4. View record in Web of Science®
  5. WOS: 000548753100045
  6. PII : 369/6500/202

Library Notes

  1. Fiscal Year: FY2019-2020
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