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

Science. 2020 Jul 10;369(6500):202-207. doi: 10.1126/science.aay5663.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factor 1 / metabolism
  • Actins / metabolism*
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Proliferation
  • Cytokines / biosynthesis*
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology
  • Lymphoproliferative Disorders / genetics*
  • Lymphoproliferative Disorders / immunology
  • Mechanistic Target of Rapamycin Complex 2 / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Pedigree
  • Phosphorylation
  • Wiskott-Aldrich Syndrome Protein Family / chemistry
  • Wiskott-Aldrich Syndrome Protein Family / metabolism

Substances

  • Actins
  • Cytokines
  • Membrane Proteins
  • WASF1 protein, human
  • WASF2 protein, human
  • WASF3 protein, human
  • Wiskott-Aldrich Syndrome Protein Family
  • NCKAP1L protein, human
  • Mechanistic Target of Rapamycin Complex 2
  • ADP-Ribosylation Factor 1
  • ARF1 protein, human