WASP and Mst1 coregulate B-cell development and B-cell receptor signaling

Abstract

Mst1 is a serine/threonine kinase involved in cell survival, proliferation, apoptosis, and tumorigenesis. In mice, Mst1 regulates actin dynamics required for T-cell adhesion and migration, which correlate with thymic egress and entry into lymphatic tissue. The role of Mst1 in B cells and how it may control actin-dependent processes has not been well characterized. Wiskott-Aldrich syndrome protein (WASP) deficiency only moderately affects development and B-cell receptor (BCR) signaling, suggesting WASP likely associates with other molecules. We investigated whether Mst1 associates with WASP to regulate B-cell development and activation. Experimenting on Mst1/WASP double knockout (DKO) mice, we found a severe defect in the bone marrow B-cell development, and BCR signaling in the DKO mice was severely reduced. Even though WASP or Mst1 could influence the early B-cell activation, we found that the early activation events such as B-cell spreading, BCR clustering, and BCR signaling were much more impaired in the B cells from DKO mice. Furthermore, reciprocal regulation between Mst1 and WASP was observed in WASP and Mst1 KO mice, whereby the localization and function of phosphorylated WASP were affected in Mst1 KO mice. Most importantly, Mst1 inhibits the expression of WASP by decreasing the expression of WASP-interacting protein. Interestingly, we also found that WASP deficiency in patients and mice interferes with phosphorylated Mst1 localization and therefore function in B cells. Overall, our study provides a partner for WASP to regulate B-cell development and BCR signaling, as well as the reciprocal regulating molecular mechanism of one another.

Involvement of MST1/mTORC1/STAT1 activity in the regulation of B‐cell receptor signalling by chemokine receptor 2

“…MST1 regulates cytoskeletal microtubule dynamics and promotes F‐actin polymerisation 29 and also modulates BCR to induce actin remodelling by attaching WASP 30 . In the absence of CCR2, the levels of pMST1, pWASP and DOCK8 were increased after sAg stimulation (Figures 4L and S7J–M).…”

“…Consistent with the augmented F-actin accumulation, the MST1 regulates cytoskeletal microtubule dynamics and promotes F-actin polymerisation 29 and also modulates BCR to induce actin remodelling by attaching WASP. 30 In the absence of CCR2, the levels of pMST1, pWASP and DOCK8 were increased after sAg stimulation (Figures 4L and S7J-M). After pre-treatment with MST1 inhibitor, XMU-MP-1, the increased expression of pmTOR, pAKT, pS6 and DOCK8 in Ccr2-KO B cells were rescued (Figure 4M).…”

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

“…The cytoskeletal defects of megakaryocytes are responsible for the low number of platelets in patients with WAS ( 92 ). WASP deficiency promotes T-cell cytoskeletal tension decay and phosphorylation of a serine/threonine protein kinase 4 (STK4) that usually increase T-cell migration, therefore promoting immune synapse breaking and secondary B cells dysfunction ( 93 , 94 ). WASP-deficient lymphocytes fails to differentiate into memory cells ( 95 ) and are more prone to develop DNA damages due to the loss of the Golgi-dispersal response, a recently described mechanism of cell survival after ionized radiation exsposure ( 96 ).…”

The Actin Regulators Involved in the Function and Related Diseases of Lymphocytes

“…For cell development, the latest studies revealed that the interaction between WASp and other signaling molecules facilitates B cell development and movement. Mst1 and WASp are significant for central and peripheral development of B cells and can adjust mutual localization and function ( 293 ). Deficiency of DOCK2 reduces the activation of WASp and accelerates its degradation, causing dysfunction of actin accumulation and affecting the early activation process of B cells ( 294 ).…”