HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease
The WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other actin-regulatory proteins modulate human immune responses, the precise role for the WRC has not yet been established. Cook et al. studied five patients from four unrelated families wh...
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| Published in | Science (American Association for the Advancement of Science) Vol. 369; no. 6500; pp. 202 - 207 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
The American Association for the Advancement of Science
10.07.2020
American Association for the Advancement of Science (AAAS) |
| Subjects | |
| Online Access | Get full text |
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| Abstract | The WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other actin-regulatory proteins modulate human immune responses, the precise role for the WRC has not yet been established. Cook
et al.
studied five patients from four unrelated families who harbor missense variants of the gene encoding the WRC component HEM1. These patients presented with recurrent infections and poor antibody responses, along with enhanced allergic and autoimmune disorders. HEM1 was found to be required for the regulation of cortical actin and granule release in T cells and also interacted with a key metabolic signaling complex contributing to the disease phenotype. By linking these interactions to immune function, this work suggests potential targets for future immunotherapies.
Science
, this issue p.
202
A study of a hereditary disease uncovers a role for HEM1 in the simultaneous regulation of F-actin and mTORC2 signaling to balance immune responses.
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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| AbstractList | An inherited disorder makes WAVEsThe WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other actin-regulatory proteins modulate human immune responses, the precise role for the WRC has not yet been established. Cook et al. studied five patients from four unrelated families who harbor missense variants of the gene encoding the WRC component HEM1. These patients presented with recurrent infections and poor antibody responses, along with enhanced allergic and autoimmune disorders. HEM1 was found to be required for the regulation of cortical actin and granule release in T cells and also interacted with a key metabolic signaling complex contributing to the disease phenotype. By linking these interactions to immune function, this work suggests potential targets for future immunotherapies.Science, this issue p. 202Immunodeficiency 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. Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this is rarely understood molecularly. We describe four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction with mutations in NCKAP1L , encoding the hematopoietic-specific HEM1 protein. These mutations cause 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 mTORC2-dependent AKT phosphorylation, T cell proliferation, and selected effector functions causing immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates F-actin and mTORC2 signaling to achieve equipoise in immune responses. A novel inborn immunodysregulatory disease reveals a role for HEM1 in independent regulation of F-actin and mTORC2 signaling. 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.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. The WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other actin-regulatory proteins modulate human immune responses, the precise role for the WRC has not yet been established. Cook et al. studied five patients from four unrelated families who harbor missense variants of the gene encoding the WRC component HEM1. These patients presented with recurrent infections and poor antibody responses, along with enhanced allergic and autoimmune disorders. HEM1 was found to be required for the regulation of cortical actin and granule release in T cells and also interacted with a key metabolic signaling complex contributing to the disease phenotype. By linking these interactions to immune function, this work suggests potential targets for future immunotherapies. Science , this issue p. 202 A study of a hereditary disease uncovers a role for HEM1 in the simultaneous regulation of F-actin and mTORC2 signaling to balance immune responses. 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. 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 , 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. |
| Author | Al Yafei, Zain ElGhazali, Gehad Chen, Baoyu Muzny, Donna M. Huang, Yanping Latour, Sylvain Cuvelier, Geoffrey D. E. Jyonouchi, Soma Cook, Sarah A. Similuk, Morgan Yang, Sheng Oler, Andrew J. Jhangiani, Shalini N. Lupski, James R. Al Hassani, Moza Caldwell, Jason W. Chinn, Ivan K. Al Kaabi, Nawal Carisey, Alexandre F. Price, Susan Poli, M. Cecilia Burkhardt, Janis K. Comrie, William A. Smelkinson, Margery Raje, Nikita Gibbs, Richard A. Faruqi, Aiman J. Kuhns, Douglas B. Orange, Jordan S. Anderson, D. Eric Abou Chahla, Wadih Coban-Akdemir, Zeynep H. Cao, Tram N. Vargas-Hernández, Alexander Fournier, Benjamin Mace, Emily M. Forbes, Lisa R. Lenardo, Michael J. Rao, V. Koneti |
| AuthorAffiliation | 1) Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD, USA 4) Program of Immunogenetics and Translational Immunology. Instituto de Ciencias e Innovación en Medicina. Facultad de Medicina Clínica Alemana-Universidad del Desarrollo, Santiago, Chile 14) Department of Pediatrics, Columbia University Irving Medical Center, New York NY 19) Sheikh Khalifa Medical City, SEHA, Abu Dhabi, United Arab Emirates 17) Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA 24) Biological Imaging Section, Research Technologies Branch, NIAID, NIH, USA 3) Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children’s Hospital, Houston, TX, USA 2) Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA 18) Pediatric Hematology-Oncology-BMT, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada 5) Division of Intramural Research, Natio |
| AuthorAffiliation_xml | – name: 15) Baylor-Hopkins Center for Mendelian Genomics, Houston, TX, USA – name: 1) Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD, USA – name: 3) Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children’s Hospital, Houston, TX, USA – name: 5) Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, 20892, USA – name: 13) Department of Pediatric Hematology, Jeanne de Flandre Hospital, CHU Lille, F-59000, France – name: 4) Program of Immunogenetics and Translational Immunology. Instituto de Ciencias e Innovación en Medicina. Facultad de Medicina Clínica Alemana-Universidad del Desarrollo, Santiago, Chile – name: 6) Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, 20892, USA – name: 26) Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA – name: 20) Division of Allergy & Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA – name: 17) Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA – name: 21) Section of Allergy/ Asthma/ Immunology, Children’s Mercy, Kansas City, Missouri, USA; University of Missouri Kansas City, Kansas City, Missouri – name: 11) Advanced Mass Spectrometry Facility, NIDDK, NIH – name: 12) Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States – name: 25) Neomics Pharmaceuticals, LLC, Gaithersburg, MD, USA – name: 9) Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR 1163, Paris F-75015 France – name: 18) Pediatric Hematology-Oncology-BMT, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada – name: 24) Biological Imaging Section, Research Technologies Branch, NIAID, NIH, USA – name: 19) Sheikh Khalifa Medical City, SEHA, Abu Dhabi, United Arab Emirates – name: 22) Section of Pulmonary, Critical Care, Allergic and Immunological Diseases, Wake Forest University School of Medicine, Winston-Salem, NC, USA – name: 14) Department of Pediatrics, Columbia University Irving Medical Center, New York NY – name: 2) Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA – name: 8) Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, USA – name: 10) University Paris Descartes Sorbonne Paris Cité, Institut des Maladies Génétiques-IMAGINE, Paris, France – name: 23) Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia Research Institute and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA – name: 7) Neutrophil Monitoring Lab, Leidos Biomedical Research, Inc., Frederick, National Laboratory for Cancer Research, Frederick, MD, USA – name: 16) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA |
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Cecilia organization: Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children’s Hospital, Houston, TX, USA., Program of Immunogenetics and Translational Immunology, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana–Universidad del Desarrollo, Santiago, Chile – sequence: 4 givenname: Morgan orcidid: 0000-0002-0403-2689 surname: Similuk fullname: Similuk, Morgan organization: Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA – sequence: 5 givenname: Andrew J. orcidid: 0000-0002-6310-0434 surname: Oler fullname: Oler, Andrew J. organization: Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD, USA – sequence: 6 givenname: Aiman J. orcidid: 0000-0002-4421-3767 surname: Faruqi fullname: Faruqi, Aiman J. organization: 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 – sequence: 7 givenname: Douglas B. orcidid: 0000-0002-9971-0760 surname: Kuhns fullname: Kuhns, Douglas B. organization: Neutrophil Monitoring Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA – sequence: 8 givenname: Sheng orcidid: 0000-0002-0321-3728 surname: Yang fullname: Yang, Sheng organization: Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, USA – sequence: 9 givenname: Alexander surname: Vargas-Hernández fullname: Vargas-Hernández, Alexander organization: Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children’s Hospital, Houston, TX, USA – sequence: 10 givenname: Alexandre F. orcidid: 0000-0003-1326-2205 surname: Carisey fullname: Carisey, Alexandre F. organization: Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children’s Hospital, Houston, TX, USA – sequence: 11 givenname: Benjamin orcidid: 0000-0002-4189-996X surname: Fournier fullname: Fournier, Benjamin organization: Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR 1163, Paris, France., University Paris Descartes Sorbonne Paris Cité, Institut des Maladies Génétiques-IMAGINE, Paris, France – sequence: 12 givenname: D. 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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC8383235 These authors contributed equally. Author contributions: W.A.C., S.A.C., and A.J.F. performed experiments related to WRC expression/function, T cell activation/function, NKL cell analysis, analyzed data, and interpreted results. S.A.C. performed experiments related to the functional validation of P359L, M371V, and V519L, patient cell microscopy, and RICTOR interaction studies. M.C.P., A.V.H., A.F.C., E.M.M., and J.S.O. directed or performed NK cell experiments, biochemical analysis of the mTORC2 complex, analyzed data, and interpreted results. D.B.K. performed neutrophil experiments and analyzed data. W.A.C. prepared immunoprecipitation-mass spectrometry (MS) samples and D.E.A. performed MS analysis and generated the list of interacting proteins. S.Y. performed in-vitro WRC reconstitution, pull-down and actin polymerization assays. M.S. acquired images and analyzed granule localization in patient cells. S.P., G.C., and V.K.R. oversaw care of Pt 1.1 and V.K.R., M.S., and A.O. performed and interpreted WES for Kindred 1. J.W.C., and N.R. oversaw care of Pts 2.1 and 2.2 and T.N.C., Z.H.C-A., S.N.J., D.M.M., R.A.G., and J.R.L. performed and interpreted WES to identify causal variants for kindred 2. M.A.H., N.A.K., Z.A.Y., S.J., and G.E. oversaw care of Pt 3.1, G.E. performed and G.E. and A.O. interpreted WES for kindred 3 to identify causal mutations. W.A.C. (2), B.F., and S.L. oversaw care of Pt 4.1 and performed and interpreted WES to identify causal mutations. Patient clinical histories were prepared by W.A.C., M.C.P., and attending physicians. J.S.O., L.R.F., J.K.B., S.L., B.C., G.E., V.K.R., I.K.C., and M.J.L. supervised various aspects of the project and project personnel. W.A.C., S.A.C., M.C.P., I.K.C., and M.J.L. interpreted results and wrote the manuscript. W.A.C. and S.A.C. took day-to-day responsibility for the study. M.J.L. coordinated the overall direction of the study. All authors read and provided appropriate feedback on the submitted manuscript. |
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| Snippet | The WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other actin-regulatory proteins modulate human... Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely... An inherited disorder makes WAVEsThe WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other... Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this is rarely understood... |
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| SubjectTerms | Actin Actins - metabolism ADP-Ribosylation Factor 1 - metabolism AKT protein Antibodies Atopy Autoimmune diseases Autoimmunity CD4-Positive T-Lymphocytes - immunology Cell adhesion & migration Cell migration Cell Proliferation Cytokines Cytokines - biosynthesis Cytoskeleton Disease control Humans Immune response Immune system Immunodeficiency Immunologic Deficiency Syndromes - genetics Immunologic Deficiency Syndromes - immunology Immunotherapy Life Sciences Lymphocytes Lymphocytes T Lymphoproliferative Disorders - genetics Lymphoproliferative Disorders - immunology Mechanistic Target of Rapamycin Complex 2 - metabolism Membrane Proteins - genetics Membrane Proteins - physiology Mutation Patients Pedigree Phenotypes Phosphorylation Proteins Rapamycin Regulatory proteins Signaling Synapses TOR protein Wiskott-Aldrich Syndrome Protein Family - chemistry Wiskott-Aldrich Syndrome Protein Family - metabolism |
| Title | HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease |
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