Department of Dermatology, University of California, San Diego, San Diego, CA, United States of America.
Department of Biological Chemistry, University of California, Irvine, Irvine, CA, United States of America.
PLoS Genet. 2018 Mar 27;14(3):e1007290. doi: 10.1371/journal.pgen.1007290. eCollection 2018 Mar.
PIKfyve, VAC14, and FIG4 form a complex that catalyzes the production of PI(3,5)P2, a signaling lipid implicated in process ranging from lysosome maturation to neurodegeneration. While previous studies have identified VAC14 and FIG4 mutations that lead to both neurodegeneration and coat color defects, how PIKfyve regulates melanogenesis is unknown. In this study, we sought to better understand the role of PIKfyve in melanosome biogenesis. Melanocyte-specific PIKfyve knockout mice exhibit greying of the mouse coat and the accumulation of single membrane vesicle structures in melanocytes resembling multivesicular endosomes. PIKfyve inhibition blocks melanosome maturation, the processing of the melanosome protein PMEL, and the trafficking of the melanosome protein TYRP1. Taken together, these studies identify a novel role for PIKfyve in controlling the delivery of proteins from the endosomal compartment to the melanosome, a role that is distinct from the role of PIKfyve in the reformation of lysosomes from endolysosomes.
PIKfyve、VAC14 和 FIG4 形成一个复合物，催化 PI(3,5)P2 的产生，该脂质参与从溶酶体成熟到神经退行性变的过程。虽然先前的研究已经确定了导致神经退行性变和毛色缺陷的 VAC14 和 FIG4 突变，但 PIKfyve 如何调节黑色素生成是未知的。在这项研究中，我们试图更好地了解 PIKfyve 在黑素体生物发生中的作用。黑素细胞特异性 PIKfyve 敲除小鼠表现出鼠毛的白化和黑素细胞中单膜囊泡结构的积累，类似于多泡内体。PIKfyve 抑制阻断黑素体成熟、黑素体蛋白 PMEL 的加工以及黑素体蛋白 TYRP1 的运输。总之，这些研究确定了 PIKfyve 在控制从内体区室向黑素体输送蛋白质中的新作用，该作用与 PIKfyve 在从内溶酶体重新形成溶酶体中的作用不同。
