Two sides of the coin: Cytoskeletal regulation of immune synapses in cancer and primary immune deficiencies

Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation

“…Coordinated regulation of actin dynamics is a prerequisite for normal B-cell responses, as is increasingly evident from the expanding recognition of primary immunodeficiency diseases with mutations in actin regulators. 15,47 Here, we studied overactive WASp in XLN patients and animal models and found that increased WASp activity leads to aberrant GC responses and premature generation of plasma cells. Our data from studying B cells with overactive WASp suggest that GC B cells with increased genomic instability may slow down proliferation and upregulate IRF4 and thereby differentiate into plasma cells faster, perhaps as a way to avoid B-cell transformation into lymphoma.…”

Journey to the Center of the Cell: Cytoplasmic and Nuclear Actin in Immune Cell Functions

“…WASp family members have a carboxy terminal verprolin cofilin acidic (VCA) domain that mediates binding to the actin related protein (Arp2/3) complex that polymerize actin branching from existing actin filaments (Campellone and Welch, 2010;Moulding et al, 2013;Alekhina et al, 2017). With increased accessibility to whole genome sequencing approaches for immunodeficient patients, patients have been described with mutations in hematopoietic protein-1 (Hem1, a component of the WAVE regulatory complex), Arp2/3 subunit Arp complex 1B (ARPC1B), Cdc42, Rac2, RhoA, and dedicator of cytokinesis 8 [Dock8, a guanine exchange factor (GEF) for Cdc42 and Rac1/2] (Saeed et al, 2020). Moreover, mutations in β-actin and the actin sensor Myocardin Related Transcription Factor A (MRTF-A)/Megakaryoblastic leukemia 1 protein (MKL1) lead to severe immunodeficiencies with poorly functional immune cells (Saeed et al, 2020).…”

“…With increased accessibility to whole genome sequencing approaches for immunodeficient patients, patients have been described with mutations in hematopoietic protein-1 (Hem1, a component of the WAVE regulatory complex), Arp2/3 subunit Arp complex 1B (ARPC1B), Cdc42, Rac2, RhoA, and dedicator of cytokinesis 8 [Dock8, a guanine exchange factor (GEF) for Cdc42 and Rac1/2] (Saeed et al, 2020). Moreover, mutations in β-actin and the actin sensor Myocardin Related Transcription Factor A (MRTF-A)/Megakaryoblastic leukemia 1 protein (MKL1) lead to severe immunodeficiencies with poorly functional immune cells (Saeed et al, 2020). As a testimony to the enormous need for rapid cell cytoskeletal adaptation, cells of the hematopoietic lineage often express multiple copies of seemingly redundant regulators of the actin cytoskeleton.…”

“…Efforts using whole genome sequencing have revealed an increasing number of diseases caused by mutations in actin regulators. This subgroup of primary immunodeficiency diseases called actinopathies provide a unique opportunity to understand how deficiency in a specific actin regulator affects immune cells (Saeed et al, 2020). The study of hematopoietic specific actin regulators has focused on their cytoplasmic role.…”

“…While stable in relation to the communicating cells, immune synapses are extremely dynamic, and sites of multiple cellular processes (Dustin, 2014). Studies of primary immunodeficiencies where patients have a mutation in specific actin regulators have provided remarkable insights into the unique and redundant functions of these regulators in immune cells (Saeed et al, 2020).…”