HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease-Reference-Cited by-同舟云学术

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

Published:2020-07-10 Issue:6500 Volume:369 Page:202-207
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Cook Sarah A.¹^ORCID,Comrie William A.¹²^ORCID,Poli M. Cecilia³⁴⁵^ORCID,Similuk Morgan⁶^ORCID,Oler Andrew J.⁷^ORCID,Faruqi Aiman J.¹^ORCID,Kuhns Douglas B.⁸^ORCID,Yang Sheng⁹^ORCID,Vargas-Hernández Alexander³⁴,Carisey Alexandre F.³⁴^ORCID,Fournier Benjamin¹⁰¹¹^ORCID,Anderson D. Eric¹²^ORCID,Price Susan¹³^ORCID,Smelkinson Margery¹⁴^ORCID,Abou Chahla Wadih¹⁵^ORCID,Forbes Lisa R.³⁴^ORCID,Mace Emily M.¹⁶^ORCID,Cao Tram N.³⁴,Coban-Akdemir Zeynep H.¹⁷¹⁸^ORCID,Jhangiani Shalini N.¹⁸¹⁹^ORCID,Muzny Donna M.¹⁸¹⁹^ORCID,Gibbs Richard A.¹⁷¹⁸¹⁹^ORCID,Lupski James R.¹⁷¹⁸¹⁹^ORCID,Orange Jordan S.¹⁶^ORCID,Cuvelier Geoffrey D. E.²⁰^ORCID,Al Hassani Moza²¹,Al Kaabi Nawal²¹,Al Yafei Zain²¹,Jyonouchi Soma²²²³,Raje Nikita²⁴²⁵,Caldwell Jason W.²⁶^ORCID,Huang Yanping²⁷²⁸,Burkhardt Janis K.²⁷^ORCID,Latour Sylvain¹⁰¹¹^ORCID,Chen Baoyu⁹^ORCID,ElGhazali Gehad²¹,Rao V. Koneti¹³^ORCID,Chinn Ivan K.³⁴^ORCID,Lenardo Michael J.¹^ORCID

Affiliation:

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.

Abstract

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

Funder

National Institutes of Health

American Diabetes Association

National Cancer Institute

National Institute of General Medical Sciences

Division of Intramural Research, National Institute of Allergy and Infectious Diseases

NIGMS

nih-nhgri

The Jeffrey Modell Foundation Translational Research Award

Publisher

American Association for the Advancement of Science (AAAS)

Subject