Rare Diseases Symptoms Automatic Extraction

N-wasp is essential for the negative regulation of B cell receptor signaling.

[wiskott-aldrich syndrome]

Negative regulation of receptor signaling is essential for controlling cell activation and differentiation. In B-lymphocytes, the down-regulation of B-cell antigen receptor (BCR) signaling is critical for suppressing the activation of self-reactive B cells; however, the mechanism underlying the negative regulation of signaling remains elusive. Using genetically manipulated mouse models and total internal reflection fluorescence microscopy, we demonstrate that neuronal Wiskott-Aldrich syndrome protein (N-WASP), which is coexpressed with WASP in all immune cells, is a critical negative regulator of B-cell signaling. B-cell-specific N-WASP gene deletion causes enhanced and prolonged BCR signaling and elevated levels of autoantibodies in the mouse serum. The increased signaling in N-WASP knockout B cells is concurrent with increased accumulation of F-actin at the B-cell surface, enhanced B-cell spreading on the antigen-presenting membrane, delayed B-cell contraction, inhibition in the merger of signaling active BCR microclusters into signaling inactive central clusters, and a blockage of BCR internalization. Upon BCR activation, WASP is activated first, followed by N-WASP in mouse and human primary B cells. The activation of N-WASP is suppressed by Bruton's tyrosine kinase-induced WASP activation, and is restored by the activation of SH2 domain-containing inositol 5-phosphatase that inhibits WASP activation. Our results reveal a new mechanism for the negative regulation of BCR signaling and broadly suggest an actin-mediated mechanism for signaling down-regulation.

Diseases presenting "elevated levels" symptom

  • 22q11.2 deletion syndrome
  • adrenal incidentaloma
  • adrenomyeloneuropathy
  • alexander disease
  • aniridia
  • cadasil
  • canavan disease
  • congenital adrenal hyperplasia
  • epidermolysis bullosa simplex
  • erythropoietic protoporphyria
  • esophageal carcinoma
  • fabry disease
  • familial hypocalciuric hypercalcemia
  • hereditary cerebral hemorrhage with amyloidosis
  • inclusion body myositis
  • kabuki syndrome
  • omenn syndrome
  • phenylketonuria
  • primary effusion lymphoma
  • pyruvate dehydrogenase deficiency
  • scrub typhus
  • sneddon syndrome
  • werner syndrome
  • wiskott-aldrich syndrome
  • wolf-hirschhorn syndrome
  • x-linked adrenoleukodystrophy
  • zellweger syndrome

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