Myosin IIA is critical for organelle distribution and F-actin organization in megakaryocytes and platelets

Abstract

Key Points• Myosin IIA deficiency affects F-actin structuration and organelle distribution in MKs which leads to abnormal platelet organelle content.During proplatelet formation, a relatively homogeneous content of organelles is transported from the megakaryocyte (MK) to the nascent platelets along microtubule tracks. We found that platelets from Myh9 2/2 mice and a MYH9-RD patient were heterogeneous in their organelle content (granules and mitochondria). In addition, Myh9 2/2 MKs have an abnormal cytoplasmic clustering of organelles, suggesting that the platelet defect originates in the MKs. Myosin is not involved in the latest stage of organelle traffic along microtubular tracks in the proplatelet shafts as shown by confocal observations of proplatelet buds. By contrast, it is required for the earlier distribution of organelles within the large MK preplatelet fragments shed into the sinusoid circulation before terminal proplatelet remodeling. We show here that F-actin is abnormally clustered in the cytoplasm of Myh9 2/2 MKs and actin polymerization is impaired in platelets. Myosin IIA is required for normal granule motility and positioning within MKs, mechanisms that may be dependent on organelle traveling and tethering onto F-actin cytoskeleton tracks. Altogether, our results indicate that the distribution of organelles within platelets critically depends on a homogeneous organelle distribution within MKs and preplatelet fragments, which requires myosin IIA. (Blood. 2014;123(8):1261-1269

Endoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore‐forming toxins

“…We show that ER and LAMP1-positive compartments localized within NMHCIIA bundles and Gp96 was proposed to modulate polarity via vesicular trafficking [35]. Additionally, NMHCIIA can control polarized secretion [37] and organelle positioning [38] and was recently shown to mediate lysosomal exocytosis in PFT-wounded cells [39]. Thus, it is possible that the link NMHCIIA-Gp96 assists the assembly of Data information: P-values were calculated using one-way ANOVA with Tukey's post hoc analyses, *P < 0.5, **P < 0.01, ***P < 0.001.…”

A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss

“…MTP and hearing loss may also cosegregate in MYH9-RD (ORPHA182050) in which abnormal expression of nonmuscle myosin heavy-chain IIA alters myosin-dependent organelle distribution and F-actin organization, thereby disrupting MK proplatelet formation. 13,14 Aberrant cytoskeletal organization in inner ear stereocilia has been proposed as a mechanism for hearing loss in MYH9-RD 16 and may contribute to this phenotype in the DIAPH1 R1213* cases. However, there are also several characteristics of the DIAPH1 R1213* cases that are absent in MYH9-RD.…”

MYH9-related inherited thrombocytopenia

“…Также при оценке мазков крови, окрашенных по Романовскому-Гимзе, у 15-84% пациентов в нейтрофилах могут быть обна-ружены специфические цитоплазматические включе-ния (белковые агрегаты аномального белка HMM-IIA) различной формы (круглые, овальные, веретеноо-бразные) и размеров, похожие на тельца Деле (рис. 4) [6,8,20,21]. В некоторых случаях эти включения могут быть не описаны из-за их мелких размеров.…”