Molecular Mechanisms of Leukocyte Migration and Its Potential Targeting—Lessons Learned From MKL1/SRF-Related Primary Immunodeficiency Diseases

Abstract

Megakaryoblastic leukemia 1 (MKL1) deficiency is one of the most recently discovered primary immunodeficiencies (PIDs) caused by cytoskeletal abnormalities. These immunological “actinopathies” primarily affect hematopoietic cells, resulting in defects in both the innate immune system (phagocyte defects) and adaptive immune system (T-cell and B-cell defects). MKL1 is a transcriptional coactivator that operates together with serum response factor (SRF) to regulate gene transcription. The MKL/SRF pathway has been originally described to have important functions in actin regulation in cells. Recent results indicate that MKL1 also has very important roles in immune cells, and that MKL1 deficiency results in an immunodeficiency affecting the migration and function of primarily myeloid cells such as neutrophils. Interestingly, several actinopathies are caused by mutations in genes which are recognized MKL(1/2)-dependent SRF-target genes, namely ACTB, WIPF1, WDR1, and MSN. Here we summarize these and related (ARPC1B) actinopathies and their effects on immune cell function, especially focusing on their effects on leukocyte adhesion and migration. Furthermore, we summarize recent therapeutic efforts targeting the MKL/SRF pathway in disease.

RNA sequencing reveals dynamic expression of spleen lncRNAs and mRNAs in Beagle dogs infected by Toxocara canis

“…The absence of WIP can affect adaptive immune cells, including B and T cells; WIP-deficient patients suffer from T-cell lymphopenia, especially CD8 + T cells [ 51 ]. In the absence of WIP, cytotoxicity can be mediated by reduction of natural killer (NK) cells and chemotaxis of B cells; however, when WIP expression is restored, these cellular alterations can be rescued [ 52 ]. In addition, WIP has been identified as an MKL (Megakaryocytic leukemia)-dependent serum response factor (SRF)-target gene [ 53 ].…”

“…In addition, WIP has been identified as an MKL (Megakaryocytic leukemia)-dependent serum response factor (SRF)-target gene [ 53 ]. MKL1 contributes to the maintenance of immune cells, which may affect the function and migration of myeloid cells [ 52 ]. At 96 hpi, the level of wipf1 gene was upregulated 1.52-fold, and the level of TCONS_00332139, located near the wipf1 gene, was downregulated 1403.09-fold.…”

MKL1 is a key biomarker correlated with immune infiltrates and chemosensitivity in breast cancer

“…For example, MKL1 deficiency impairs the function of the immune system and results in primary immunodeficiency. The migration and function of neutrophils are affected by the dysfunction of actin polymerization (16,17).…”

Metabolic Signature-Based Subtypes May Pave Novel Ways for Low-Grade Glioma Prognosis and Therapy

“…BTK was a non-receptor kinase belonging to the Tec family of kinases which played a vital role in the proliferation and survival of malignant activities ( Ahn and Brown, 2021 ). ARPC1B played an essential role in the maintenance and assembly of the ARP2/3 complex and could function in multiple cellular activities, such as cell migration, progression, and DNA repair ( Sprenkeler et al, 2021 ). ALOX5 and its metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) were involved in tumorigenesis, development, and metastasis ( Weigert et al, 2018 ).…”