Sprenkeler Evelien G G, Guenther Carla, Faisal Imrul, Kuijpers Taco W, Fagerholm Susanna C
Department of Blood Cell Research, Sanquin Research, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, Netherlands.
Department of Pediatric Immunology, Rheumatology, and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Center (AUMC), University of Amsterdam, Amsterdam, Netherlands.
Front Immunol. 2021 Feb 22;12:615477. doi: 10.3389/fimmu.2021.615477. eCollection 2021.
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 , , , and . 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.
巨核细胞白血病1（MKL1）缺陷是最近发现的由细胞骨架异常引起的原发性免疫缺陷（PID）之一。这些免疫性“肌动蛋白病”主要影响造血细胞，导致先天性免疫系统（吞噬细胞缺陷）和适应性免疫系统（T细胞和B细胞缺陷）出现缺陷。MKL1是一种转录共激活因子，与血清反应因子（SRF）共同作用以调节基因转录。MKL/SRF途径最初被描述为在细胞肌动蛋白调节中具有重要功能。最近的研究结果表明，MKL1在免疫细胞中也具有非常重要的作用，并且MKL1缺陷会导致免疫缺陷，主要影响中性粒细胞等髓系细胞的迁移和功能。有趣的是，几种肌动蛋白病是由被认为是MKL（1/2）依赖性SRF靶基因的基因突变引起的，即 、 、 和 。在这里，我们总结这些以及相关的（ARPC1B）肌动蛋白病及其对免疫细胞功能的影响，尤其关注它们对白细胞黏附和迁移的影响。此外，我们总结了最近针对疾病中MKL/SRF途径的治疗研究。
