Advertisement
No access
Report

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

Sarah A. Cook https://orcid.org/0000-0002-2923-4009, William A. Comrie https://orcid.org/0000-0003-1173-1127, M. Cecilia Poli https://orcid.org/0000-0001-6817-0573, Morgan Similuk https://orcid.org/0000-0002-0403-2689, Andrew J. Oler https://orcid.org/0000-0002-6310-0434, Aiman J. Faruqi https://orcid.org/0000-0002-4421-3767, Douglas B. Kuhns https://orcid.org/0000-0002-9971-0760, Sheng Yang https://orcid.org/0000-0002-0321-3728, Alexander Vargas-Hernández, Alexandre F. Carisey https://orcid.org/0000-0003-1326-2205, Benjamin Fournier https://orcid.org/0000-0002-4189-996X, D. Eric Anderson https://orcid.org/0000-0002-6838-0201, Susan Price https://orcid.org/0000-0002-1004-8441, Margery Smelkinson https://orcid.org/0000-0001-7777-5574, Wadih Abou Chahla https://orcid.org/0000-0002-8170-0951, Lisa R. Forbes https://orcid.org/0000-0001-9402-1934, Emily M. Mace https://orcid.org/0000-0003-0226-7393, Tram N. Cao, Zeynep H. Coban-Akdemir https://orcid.org/0000-0001-9928-9032, Shalini N. Jhangiani https://orcid.org/0000-0002-6674-0074, Donna M. Muzny https://orcid.org/0000-0002-3055-0359, Richard A. Gibbs https://orcid.org/0000-0002-1356-5698, James R. Lupski https://orcid.org/0000-0001-9907-9246, Jordan S. Orange https://orcid.org/0000-0001-7117-7725, Geoffrey D. E. Cuvelier https://orcid.org/0000-0003-4493-8757, Moza Al Hassani, Nawal Al Kaabi, Zain Al Yafei, Soma Jyonouchi, Nikita Raje, Jason W. Caldwell https://orcid.org/0000-0003-4617-8982, Yanping Huang, Janis K. Burkhardt https://orcid.org/0000-0002-8176-1375, Sylvain Latour https://orcid.org/0000-0001-8238-4391, Baoyu Chen https://orcid.org/0000-0002-6366-159X, Gehad ElGhazali, V. Koneti Rao https://orcid.org/0000-0002-7881-6902, Ivan K. Chinn https://orcid.org/0000-0001-5684-5457, and Michael J. Lenardo https://orcid.org/0000-0003-1584-468X [email protected]Authors Info & Affiliations
Science
10 Jul 2020
Vol 369, Issue 6500
pp. 202-207

An inherited disorder makes WAVEs

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

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.

Get full access to this article

View all available purchase options and get full access to this article.

Supplementary Material

Summary

Materials and Methods
Supplementary Text
Figs. S1 to S12
Tables S1 to S6
References (3042)
Movies S1 to S4

Resources

File (aay5663_cook_sm.pdf)
File (aay5663_s1.mov)
File (aay5663_s2.mov)
File (aay5663_s3.mov)
File (aay5663_s4.mov)
File (aay5663_tables3.xlsx)
File (aay5663_tables5.xlsx)

References and Notes

1
C. Cunningham-Rundles, P. P. Ponda, Molecular defects in T- and B-cell primary immunodeficiency diseases. Nat. Rev. Immunol. 5, 880–892 (2005).
2
R. A. Saxton, D. M. Sabatini, mTOR Signaling in Growth, Metabolism, and Disease. Cell 169, 361–371 (2017).
3
D. A. Guertin, D. M. Stevens, C. C. Thoreen, A. A. Burds, N. Y. Kalaany, J. Moffat, M. Brown, K. J. Fitzgerald, D. M. Sabatini, Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev. Cell 11, 859–871 (2006).
4
K. Lee, P. Gudapati, S. Dragovic, C. Spencer, S. Joyce, N. Killeen, M. A. Magnuson, M. Boothby, Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32, 743–753 (2010).
5
L. A. Van de Velde, P. J. Murray, Proliferating Helper T Cells Require Rictor/mTORC2 Complex to Integrate Signals from Limiting Environmental Amino Acids. J. Biol. Chem. 291, 25815–25822 (2016).
6
B. Chen, S. B. Padrick, L. Henry, M. K. Rosen, Biochemical reconstitution of the WAVE regulatory complex. Methods Enzymol. 540, 55–72 (2014).
7
T. E. Stradal, K. Rottner, A. Disanza, S. Confalonieri, M. Innocenti, G. Scita, Regulation of actin dynamics by WASP and WAVE family proteins. Trends Cell Biol. 14, 303–311 (2004).
8
B. Chen, H.-T. Chou, C. A. Brautigam, W. Xing, S. Yang, L. Henry, L. K. Doolittle, T. Walz, M. K. Rosen, Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites. eLife 6, e29795 (2017).
9
Z. Chen, D. Borek, S. B. Padrick, T. S. Gomez, Z. Metlagel, A. M. Ismail, J. Umetani, D. D. Billadeau, Z. Otwinowski, M. K. Rosen, Structure and control of the actin regulatory WAVE complex. Nature 468, 533–538 (2010).
10
A. M. Lebensohn, M. W. Kirschner, Activation of the WAVE complex by coincident signals controls actin assembly. Mol. Cell 36, 512–524 (2009).
11
C. Litschko, J. Linkner, S. Brühmann, T. E. B. Stradal, T. Reinl, L. Jänsch, K. Rottner, J. Faix, Differential functions of WAVE regulatory complex subunits in the regulation of actin-driven processes. Eur. J. Cell Biol. 96, 715–727 (2017).
12
L. Shao, J. Chang, W. Feng, X. Wang, E. A. Williamson, Y. Li, A. Schajnovitz, D. Scadden, L. J. Mortensen, C. P. Lin, L. Li, A. Paulson, J. Downing, D. Zhou, R. A. Hromas, The Wave2 scaffold Hem-1 is required for transition of fetal liver hematopoiesis to bone marrow. Nat. Commun. 9, 2377 (2018).
13
S. O. Burns, A. Zarafov, A. J. Thrasher, Primary immunodeficiencies due to abnormalities of the actin cytoskeleton. Curr. Opin. Hematol. 24, 16–22 (2017).
14
M. Kircher, D. M. Witten, P. Jain, B. J. O’Roak, G. M. Cooper, J. Shendure, A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315 (2014).
15
H. Park, K. Staehling-Hampton, M. W. Appleby, M. E. Brunkow, T. Habib, Y. Zhang, F. Ramsdell, H. D. Liggitt, B. Freie, M. Tsang, G. Carlson, S. Friend, C. Frevert, B. M. Iritani, A point mutation in the murine Hem1 gene reveals an essential role for Hematopoietic protein 1 in lymphopoiesis and innate immunity. J. Exp. Med. 205, 2899–2913 (2008).
16
A. Leithner, A. Eichner, J. Müller, A. Reversat, M. Brown, J. Schwarz, J. Merrin, D. J. J. de Gorter, F. Schur, J. Bayerl, I. de Vries, S. Wieser, R. Hauschild, F. P. L. Lai, M. Moser, D. Kerjaschki, K. Rottner, J. V. Small, T. E. B. Stradal, M. Sixt, Diversified actin protrusions promote environmental exploration but are dispensable for locomotion of leukocytes. Nat. Cell Biol. 18, 1253–1259 (2016).
17
C. Basquin, M. Trichet, H. Vihinen, V. Malardé, T. Lagache, L. Ripoll, E. Jokitalo, J.-C. Olivo-Marin, A. Gautreau, N. Sauvonnet, Membrane protrusion powers clathrin-independent endocytosis of interleukin-2 receptor. EMBO J. 34, 2147–2161 (2015).
18
A. F. Carisey, E. M. Mace, M. B. Saeed, D. M. Davis, J. S. Orange, Nanoscale dynamism of actin enables secretory function in cytolytic cells. Curr. Biol. 28, 489–502.e9 (2018).
19
A. Gil-Krzewska, M. B. Saeed, A. Oszmiana, E. R. Fischer, K. Lagrue, W. A. Gahl, W. J. Introne, J. E. Coligan, D. M. Davis, K. Krzewski, An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome. J. Allergy Clin. Immunol. 142, 914–927.e6 (2018).
20
S. Murugesan, J. Hong, J. Yi, D. Li, J. R. Beach, L. Shao, J. Meinhardt, G. Madison, X. Wu, E. Betzig, J. A. Hammer, Formin-generated actomyosin arcs propel T cell receptor microcluster movement at the immune synapse. J. Cell Biol. 215, 383–399 (2016).
21
J. C. Nolz, T. S. Gomez, P. Zhu, S. Li, R. B. Medeiros, Y. Shimizu, J. K. Burkhardt, B. D. Freedman, D. D. Billadeau, The WAVE2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr. Biol. 16, 24–34 (2006).
22
O. D. Weiner, M. C. Rentel, A. Ott, G. E. Brown, M. Jedrychowski, M. B. Yaffe, S. P. Gygi, L. C. Cantley, H. R. Bourne, M. W. Kirschner, Hem-1 complexes are essential for Rac activation, actin polymerization, and myosin regulation during neutrophil chemotaxis. PLOS Biol. 4, e38 (2006).
23
J. C. Nolz, R. B. Medeiros, J. S. Mitchell, P. Zhu, B. D. Freedman, Y. Shimizu, D. D. Billadeau, WAVE2 regulates high-affinity integrin binding by recruiting vinculin and talin to the immunological synapse. Mol. Cell. Biol. 27, 5986–6000 (2007).
24
J. C. Nolz, L. P. Nacusi, C. M. Segovis, R. B. Medeiros, J. S. Mitchell, Y. Shimizu, D. D. Billadeau, The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL-C3G-mediated activation of Rap1. J. Cell Biol. 182, 1231–1244 (2008).
25
D. D. Sarbassov, D. A. Guertin, S. M. Ali, D. M. Sabatini, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).
26
A. Diz-Muñoz, K. Thurley, S. Chintamen, S. J. Altschuler, L. F. Wu, D. A. Fletcher, O. D. Weiner, Membrane Tension Acts Through PLD2 and mTORC2 to Limit Actin Network Assembly During Neutrophil Migration. PLOS Biol. 14, e1002474 (2016).
27
B. Treanor, D. Depoil, A. Gonzalez-Granja, P. Barral, M. Weber, O. Dushek, A. Bruckbauer, F. D. Batista, The membrane skeleton controls diffusion dynamics and signaling through the B cell receptor. Immunity 32, 187–199 (2010).
28
T. N. Iwata, J. A. Ramírez-Komo, H. Park, B. M. Iritani, Control of B lymphocyte development and functions by the mTOR signaling pathways. Cytokine Growth Factor Rev. 35, 47–62 (2017).
29
C. Yang, S.-W. Tsaih, A. Lemke, M. J. Flister, M. S. Thakar, S. Malarkannan, mTORC1 and mTORC2 differentially promote natural killer cell development. eLife 7, e35619 (2018).
30
U. Paila, B. A. Chapman, R. Kirchner, A. R. Quinlan, GEMINI: Integrative exploration of genetic variation and genome annotations. PLOS Comput. Biol. 9, e1003153 (2013).
31
M. Lek, K. J. Karczewski, E. V. Minikel, K. E. Samocha, E. Banks, T. Fennell, A. H. O’Donnell-Luria, J. S. Ware, A. J. Hill, B. B. Cummings, T. Tukiainen, D. P. Birnbaum, J. A. Kosmicki, L. E. Duncan, K. Estrada, F. Zhao, J. Zou, E. Pierce-Hoffman, J. Berghout, D. N. Cooper, N. Deflaux, M. DePristo, R. Do, J. Flannick, M. Fromer, L. Gauthier, J. Goldstein, N. Gupta, D. Howrigan, A. Kiezun, M. I. Kurki, A. L. Moonshine, P. Natarajan, L. Orozco, G. M. Peloso, R. Poplin, M. A. Rivas, V. Ruano-Rubio, S. A. Rose, D. M. Ruderfer, K. Shakir, P. D. Stenson, C. Stevens, B. P. Thomas, G. Tiao, M. T. Tusie-Luna, B. Weisburd, H.-H. Won, D. Yu, D. M. Altshuler, D. Ardissino, M. Boehnke, J. Danesh, S. Donnelly, R. Elosua, J. C. Florez, S. B. Gabriel, G. Getz, S. J. Glatt, C. M. Hultman, S. Kathiresan, M. Laakso, S. McCarroll, M. I. McCarthy, D. McGovern, R. McPherson, B. M. Neale, A. Palotie, S. M. Purcell, D. Saleheen, J. M. Scharf, P. Sklar, P. F. Sullivan, J. Tuomilehto, M. T. Tsuang, H. C. Watkins, J. G. Wilson, M. J. Daly, D. G. MacArthur, Exome Aggregation Consortium, Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
32
K. B. Sanborn, G. D. Rak, S. Y. Maru, K. Demers, A. Difeo, J. A. Martignetti, M. R. Betts, R. Favier, P. P. Banerjee, J. S. Orange, Myosin IIA associates with NK cell lytic granules to enable their interaction with F-actin and function at the immunological synapse. J. Immunol. 182, 6969–6984 (2009).
33
K. B. Sanborn, G. D. Rak, A. N. Mentlik, P. P. Banerjee, J. S. Orange, Analysis of the NK cell immunological synapse. Methods Mol. Biol. 612, 127–148 (2010).
34
P. P. Banerjee, J. S. Orange, Quantitative measurement of F-actin accumulation at the NK cell immunological synapse. J. Immunol. Methods 355, 1–13 (2010).
35
J. Schindelin, I. Arganda-Carreras, E. Frise, V. Kaynig, M. Longair, T. Pietzsch, S. Preibisch, C. Rueden, S. Saalfeld, B. Schmid, J.-Y. Tinevez, D. J. White, V. Hartenstein, K. Eliceiri, P. Tomancak, A. Cardona, Fiji: An open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).
36
E. K. O’Shea, K. J. Lumb, P. S. Kim, Peptide ‘Velcro’: Design of a heterodimeric coiled coil. Curr. Biol. 3, 658–667 (1993).
37
E. C. Keilhauer, M. Y. Hein, M. Mann, Accurate protein complex retrieval by affinity enrichment mass spectrometry (AE-MS) rather than affinity purification mass spectrometry (AP-MS). Mol. Cell. Proteomics 14, 120–135 (2015).
38
P. J. Boersema, R. Raijmakers, S. Lemeer, S. Mohammed, A. J. Heck, Multiplex peptide stable isotope dimethyl labeling for quantitative proteomics. Nat. Protoc. 4, 484–494 (2009).
39
J. Cox, M. Mann, MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008).
40
Y. Lin, L. Huo, Z. Liu, J. Li, Y. Liu, Q. He, X. Wang, S. Liang, Sodium laurate, a novel protease- and mass spectrometry-compatible detergent for mass spectrometry-based membrane proteomics. PLOS ONE 8, e59779 (2013).
41
J. Rappsilber, M. Mann, Y. Ishihama, Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat. Protoc. 2, 1896–1906 (2007).
42
C. L. Perrin, B. K. Ohta, J. Kuperman, Beta-deuterium isotope effects on amine basicity, “inductive” and stereochemical. J. Am. Chem. Soc. 125, 15008–15009 (2003).

(0)eLetters

eLetters is an online forum for ongoing peer review. Submission of eLetters are open to all. eLetters are not edited, proofread, or indexed. Please read our Terms of Service before submitting your own eLetter.

Log In to Submit a Response

No eLetters have been published for this article yet.

Information & Authors

Information

Published In

Science
Volume 369 | Issue 6500
10 July 2020

Submission history

Received: 30 June 2019
Accepted: 29 May 2020
Published in print: 10 July 2020

Permissions

Request permissions for this article.

Acknowledgments

The authors thank the patients and family members for participating in this study and making this research possible. We thank H. Su for scientific input, discussions, and careful reading of the manuscript. The authors thank members of the Bioinformatics and Computational Biosciences Branch (BCBB), NIAID for bioinformatics support; the Office of Cyber Infrastructure and Computational Biology (OCICB), NIAID for high-performance computing support; and the Laboratory of Immune System Biology Flow Cytometry Core, NIAID for cell analysis. Finally, we thank the staff of the Advanced Mass Spectrometry Core, NIDDK. Funding: This work was supported by the Jeffrey Model Foundation Translational Research Award to I.K.C.; NIH-NIAID grant R01 AI120989 to J.S.O.; NIH-NIGMS (National Institute of General Medical Sciences) grant R35 GM128786 and start-up funds from the Iowa State University and the Roy J. Carver Charitable Trust to B.C.; NIH-NHGRI (National Human Genome Research Institute) grant UM1 HG006542 to the Baylor-Hopkins Center for Mendelian Genomics; and the National Cancer Institute, NIH, under contract no. HHSN261200800001E. Additional support came from the Division of Intramural Research, NIAID, NIH; the Division of Intramural Research, NIDDK; and the Deputy Director of Intramural Research, NIH, through the Clinical Center Genomics Opportunity. This work was also funded by a fellowship grant (1-16-PDF-025 to W.A.Co.) from the American Diabetes Association and a F12 postdoctoral fellowship (1FI2GM119979-01 to W.A.Co.) from the NIGMS, NIH. M.C.P. was supported by the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT no. 11181222). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. Author contributions: W.A.Co., S.A.C., and A.J.F. performed experiments related to WRC expression and function, T cell activation and function, and 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 and biochemical analysis of the mTORC2 complex, analyzed data, and interpreted results. D.B.K. performed neutrophil experiments and analyzed data. W.A.Co. prepared IP-MS samples, and D.E.A. performed MS analysis and generated the list of interacting proteins. S.Y. performed in vitro WRC reconstitution and pull-down and actin polymerization assays. M.Sm. acquired images and analyzed granule localization in patient cells. S.P., G.D.E.C., and V.K.R. oversaw care of Pt 1.1, and V.K.R., M.Si., and A.J.O. performed and interpreted whole-exome sequencing (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.J.O. interpreted WES for kindred 3 to identify causal mutations. W.A.Ch., 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.Co., 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.Co., S.A.C., M.C.P., I.K.C., and M.J.L. interpreted results and wrote the manuscript. W.A.Co. 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. Competing interests: N.R. is a consultant for Horizon Therapeutics. Data and materials availability: All data needed to evaluate the conclusions in this paper are present either in the main text or the supplementary materials. WES data for the kindred of Pt 1.1 were submitted to the National Center for Biotechnology Information’s (NCBI) database of Genotypes and Phenotypes (dbGaP) (accession no., phs001561). WES data for the kindred of Pts 2.1 and 2.2 were submitted to dbGaP (accession no., phs000711).

Authors

Affiliations

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.
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’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.
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.
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.
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.
Alexander Vargas-Hernández
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children’s Hospital, Houston, TX, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children’s Hospital, Houston, TX, USA.
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.
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, Baylor College of Medicine, Houston, TX, USA.
Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children’s Hospital, Houston, TX, USA.
Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
Tram N. Cao
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children’s Hospital, Houston, TX, USA.
Baylor-Hopkins Center for Mendelian Genomics, Houston, TX, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, 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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 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.
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.
Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
Section of Pediatric Hematology/Oncology/BMT, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.
Moza Al Hassani
Sheikh Khalifa Medical City, Abu Dhabi Healthcare Company (SEHA), Abu Dhabi, United Arab Emirates.
Nawal Al Kaabi
Sheikh Khalifa Medical City, Abu Dhabi Healthcare Company (SEHA), Abu Dhabi, United Arab Emirates.
Zain Al Yafei
Sheikh Khalifa Medical City, Abu Dhabi Healthcare Company (SEHA), Abu Dhabi, United Arab Emirates.
Soma Jyonouchi
Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nikita Raje
Division of Allergy, Immunology, Pulmonary, and Sleep Medicine, Children’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.
Yanping Huang
Department of Pathology and Laboratory Medicine, Children'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.
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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.
Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, USA.
Gehad ElGhazali
Sheikh Khalifa Medical City, Abu Dhabi Healthcare Company (SEHA), Abu Dhabi, United Arab Emirates.
Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Section of Pediatric Immunology, Allergy, and Retrovirology, Texas Children’s Hospital, Houston, TX, 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.

Funding Information

National Cancer Institute: No. HHSN261200800001E
NIGMS: 1FI2GM119979-01
nih-nhgri: UM1 HG006542
The Jeffrey Modell Foundation Translational Research Award

Notes

*
These authors contributed equally to this work.
Corresponding author. Email: [email protected]

Metrics & Citations

Metrics

Article Usage
Altmetrics

Citations

Export citation

Select the format you want to export the citation of this publication.

Cited by

  1. The actin-regulatory protein Hem-1 is essential for alveolar macrophage development, Journal of Experimental Medicine, 218, 4, (2021).https://doi.org/10.1084/jem.20200472
    Crossref
  2. WAVE regulatory complex, Current Biology, 31, 10, (R512-R517), (2021).https://doi.org/10.1016/j.cub.2021.01.086
    Crossref
  3. Functional genetics in inborn errors of immunity, Future Rare Diseases, 1, 2, (FRD11), (2021).https://doi.org/10.2217/frd-2020-0003
    Crossref
  4. mTOR-Mediated Cell Death and Infection, Infectious Microbes and Diseases, 3, 2, (57-68), (2021).https://doi.org/10.1097/IM9.0000000000000063
    Crossref
  5. Cytoskeletal control of the secretory immune synapse, Current Opinion in Cell Biology, 71, (87-94), (2021).https://doi.org/10.1016/j.ceb.2021.02.008
    Crossref
  6. Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrin-mediated adhesion, Current Biology, 31, 10, (2051-2064.e8), (2021).https://doi.org/10.1016/j.cub.2021.02.043
    Crossref
  7. The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee, Journal of Clinical Immunology, 41, 3, (666-679), (2021).https://doi.org/10.1007/s10875-021-00980-1
    Crossref
  8. Combined Immunodeficiencies, Cellular Primary Immunodeficiencies, (75-96), (2021).https://doi.org/10.1007/978-3-030-70107-9_6
    Crossref
  9. Molecular mechanisms of phenotypic variability in monogenic autoinflammatory diseases, Nature Reviews Rheumatology, 17, 7, (405-425), (2021).https://doi.org/10.1038/s41584-021-00614-1
    Crossref
  10. WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity, Science, 371, 6536, (2021)./doi/10.1126/science.aaz4544
    Abstract
  11. See more
Loading...

View Options

Check Access

Log in to view the full text

AAAS ID LOGIN

AAAS login provides access to Science for AAAS Members, and access to other journals in the Science family to users who have purchased individual subscriptions.

Log in via OpenAthens.
Log in via Shibboleth.
More options

Register for free to read this article

As a service to the community, this article is available for free. Login or register for free to read this article.

Purchase this issue in print

Buy a single issue of Science for just $15 USD.

View options

PDF format

Download this article as a PDF file

Download PDF

Full Text

FULL TEXT

Media

Figures

Multimedia

Tables

Share

Share

Share article link

Share on social media