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

• Published in: Science (American Association for the Advancement of Science) Vol. 369; no. 6500; pp. 202 - 207
• Main Authors: Cook, Sarah A., Comrie, William A., Poli, M. Cecilia, Similuk, Morgan, Oler, Andrew J., Faruqi, Aiman J., Kuhns, Douglas B., Yang, Sheng, Vargas-Hernández, Alexander, Carisey, Alexandre F., Fournier, Benjamin, Anderson, D. Eric, Price, Susan, Smelkinson, Margery, Abou Chahla, Wadih, Forbes, Lisa R., Mace, Emily M., Cao, Tram N., Coban-Akdemir, Zeynep H., Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lupski, James R., Orange, Jordan S., Cuvelier, Geoffrey D. E., Al Hassani, Moza, Al Kaabi, Nawal, Al Yafei, Zain, Jyonouchi, Soma, Raje, Nikita, Caldwell, Jason W., Huang, Yanping, Burkhardt, Janis K., Latour, Sylvain, Chen, Baoyu, ElGhazali, Gehad, Rao, V. Koneti, Chinn, Ivan K., Lenardo, Michael J.
• 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: 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
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aay5663

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.