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ACKNOWLEDGMENTS
The authors thank M. Ardyna and M. M. Mills for their constructive
comments on initial versions of the manuscript.Funding:This
work is supported by NASA Earth and Space Science Fellowship
grant NNX16AO08H awarded to K.M.L., NASA Earth and Space
Science Fellowship grant RR175-257-4945576 awarded to K.R.A.,
and National Science Foundation grant 1304563 awarded to
K.R.A.Author contributions:K.M.L. was responsible for formal
analysis, funding acquisition, investigation, and writing (original
draft). G.L.v.D. was responsible for data curation, investigation,
software, formal analysis, and writing (reviewing and editing). K.R.A.
was responsible for conceptualization, investigation, supervision,and writing (reviewing and editing).Competing interests:The
authors have no competing interests.Data and materials availability:
Bio-optical data used to develop the Arctic Chlaalgorithm as well as
time series data for Chla, NPP, SST, OW area, and OW duration can
be found on the Dryad data repository ( 35 ).SUPPLEMENTARY MATERIALS
science.sciencemag.org/content/369/6500/198/suppl/DC1
Materials and Methods
Supplementary Text
Figs. S1 to S6
References ( 36 – 44 )
24 July 2019; accepted 15 May 2020
10.1126/science.aay8380IMMUNODEFICIENCIES
HEM1 deficiency disrupts mTORC2 and F-actin control
ininherited immunodysregulatory disease
Sarah A. Cook^1 , William A. Comrie1,2, M. Cecilia Poli3,4,5, Morgan Similuk^6 , Andrew J. Oler^7 ,
Aiman J. Faruqi^1 , Douglas B. Kuhns^8 , Sheng Yang^9 , Alexander Vargas-Hernández3,4,
Alexandre F. Carisey3,4, Benjamin Fournier10,11, D. Eric Anderson^12 , Susan Price^13 ,
Margery Smelkinson^14 , Wadih Abou Chahla^15 , Lisa R. Forbes3,4, Emily M. Mace^16 , Tram N. Cao3,4,
Zeynep H. Coban-Akdemir17,18, Shalini N. Jhangiani18,19, Donna M. Muzny18,19, Richard A. Gibbs17,18,19,
James R. Lupski17,18,19, Jordan S. Orange^16 , Geoffrey D. E. Cuvelier^20 , Moza Al Hassani^21 ,
Nawal Al Kaabi^21 , Zain Al Yafei^21 , Soma Jyonouchi22,23, Nikita Raje24,25, Jason W. Caldwell^26 ,
Yanping Huang27,28, Janis K. Burkhardt^27 , Sylvain Latour10,11, Baoyu Chen^9 , Gehad ElGhazali^21 ,
V. Koneti Rao^13 , Ivan K. Chinn3,4, Michael J. Lenardo^1 †
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 inNCKAP1L, 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.
I
nborn errors of immunity (IEIs) can affect
global cellular regulatory systems ( 1 ). The
mechanistic target of rapamycin complex 1
(mTORC1) and mTORC2 are global regu-
lators of metabolism and cell signaling.mTORC2, comprising the mTOR, RICTOR,
mSIN1, mLST8, PROTOR1 and PROTOR2
(PROTOR1/2), and DEPTOR proteins, activates
AGC kinases downstream of phosphoinositide
3-kinase (PI3K) to promote T cell survival, pro-liferation, and differentiation ( 2 – 5 ). Similarly,
actin is a global regulator of cellular behavior
and immune synapse (IS) formation ( 6 , 7 ). Sig-
nals activating the WAVE regulatory complex
(WRC), which contains CYFIP1/2, HEM1/2, ABI1/
2/3, HSPC300, and WAVE1/2/3, control the
dynamics of Arp2/3-mediated branched fila-
mentous actin (F-actin) nucleation and poly-
merization. In the WRC, HEM1/2 and CYFIP1/2
form a membrane-associated scaffold support-
ing the ABI1/2, HSPC300, and WAVE1/2/3
proteins and are directly activated by the small
guanosine triphosphatases (GTPases) Rac1 and
Arf1, although the Arf1 binding site is uncertain
( 8 , 9 ) (Fig. 1). Whether the WRC regulates the
cortical actin network (CAcN) is unknown
( 6 – 12 ). Mutations affecting actin regulatory
proteins underlie immunodeficiencies (table
S1), but none have been reported yet for WRC
components ( 13 ).
We investigated five patients from four un-
related families with recurrent bacterial and
viral skin infections, severe respiratory tract
infections leading to pneumonia and bron-
chiectasis (Fig. 1, A and B, left panels, and fig.
S1A), and poor specific antibody responses
(Fig. 1B, right panel, and table S2). Paradox-
ically, these patients also exhibited atopic and
inflammatory disease alongside chronic hep-
atosplenomegaly and lymphadenopathy, some-
times with elevated immunoglobulin E (IgE) or
IgG and autoimmune manifestations (Fig. 1B;
fig. S1, B and C; and tables S2 and S3). FoxP3+
T regulatory cells were normal (fig. S1D). All202 10 JULY 2020•VOL 369 ISSUE 6500 sciencemag.org SCIENCE
(^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.
*These authors contributed equally to this work.
†Corresponding author. Email: [email protected]
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