| First Author | Dai J | Year | 2016 |
| Journal | J Pathol | Volume | 240 |
| Issue | 1 | Pages | 108-19 |
| PubMed ID | 27319744 | Mgi Jnum | J:241545 |
| Mgi Id | MGI:5902907 | Doi | 10.1002/path.4762 |
| Citation | Dai J, et al. (2016) Vps33b regulates Vwf-positive vesicular trafficking in megakaryocytes. J Pathol 240(1):108-19 |
| abstractText | Mutations of vacuolar protein sorting-associated protein 33b (VPS33B) cause arthrogryposis, renal dysfunction, and cholestasis syndrome, and a lack of platelet alpha-granules in the affected patients. Conditional Vps33b knockout mice were developed to investigate the function(s) of Vps33b in platelet alpha-granule formation. We found that early embryonic deletion of Vps33b was lethal. PF4-Cre-driven megakaryocyte-targeted Vps33b gene deletion greatly diminished Vps33b expression in platelets, but had no effect on platelet alpha-granule formation and protein content. Tamoxifen-induced, haematopoietic stem cell (HSC)-specific Vps33b deletion completely depleted Vps33b in platelets, caused the absence of alpha-granules, and increased the number of vacuoles in platelets and megakaryocytes. VPS33B association with VIPAS39, alpha-tubulin, and SEC22B was identified by co-immunoprecipitation, mass spectra, and immunoblotting in human embryonic kidney 293T (HEK293T) cells. Also, pull-down experiments revealed that VIPAS39 bound to intact VPS33B; in contrast, alpha-tubulin and SEC22B separately interacted with the sec1-like domains of VPS33B. Vps33b deficiency in megakaryocytes disturbs the redistribution of Vipas39 and Sec22b to proplatelets, and interrupted the co-localization of Sec22b with Vwf-positive vesicles. The data presented in this study suggest that Vps33b is involved in alpha-granule formation possibly by facilitating the Vwf-positive vesicular trafficking to alpha-granule-related vacuoles in megakaryocytes. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
