Delevoye Cédric, Heiligenstein Xavier, Ripoll Léa, Gilles-Marsens Floriane, Dennis Megan K, Linares Ricardo A, Derman Laura, Gokhale Avanti, Morel Etienne, Faundez Victor, Marks Michael S, Raposo Graça
Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, 75005 Paris, France; Institut Curie, PSL Research University, CNRS, UMR144, Cell and Tissue Imaging Facility (PICT-IBiSA), 75005 Paris, France.
Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, 75005 Paris, France.
Curr Biol. 2016 Jan 11;26(1):1-13. doi: 10.1016/j.cub.2015.11.020. Epub 2015 Dec 24.
Recycling endosomes consist of a tubular network that emerges from vacuolar sorting endosomes and diverts cargoes toward the cell surface, the Golgi, or lysosome-related organelles. How recycling tubules are formed remains unknown. We show that recycling endosome biogenesis requires the protein complex BLOC-1. Mutations in BLOC-1 subunits underlie an inherited disorder characterized by albinism, the Hermansky-Pudlak Syndrome, and are associated with schizophrenia risk. We show here that BLOC-1 coordinates the kinesin KIF13A-dependent pulling of endosomal tubules along microtubules to the Annexin A2/actin-dependent stabilization and detachment of recycling tubules. These components cooperate to extend, stabilize and form tubular endosomal carriers that function in cargo recycling and in the biogenesis of pigment granules in melanocytic cells. By shaping recycling endosomal tubules, our data reveal that dysfunction of the BLOC-1-KIF13A-Annexin A2 molecular network underlies the pathophysiology of neurological and pigmentary disorders.
再循环内体由一个管状网络组成，该网络从液泡分选内体中产生，并将货物导向细胞表面、高尔基体或溶酶体相关细胞器。再循环小管是如何形成的仍然未知。我们发现再循环内体的生物发生需要蛋白质复合物BLOC-1。BLOC-1亚基的突变是一种以白化病为特征的遗传性疾病——赫尔曼斯基-普德拉克综合征的基础，并且与精神分裂症风险相关。我们在此表明，BLOC-1协调驱动蛋白KIF13A依赖的内体小管沿微管向膜联蛋白A2/肌动蛋白依赖的再循环小管的稳定和脱离的牵引。这些成分协同作用以延伸、稳定并形成管状内体载体，这些载体在货物再循环和黑素细胞中色素颗粒的生物发生中发挥作用。通过塑造再循环内体小管，我们的数据揭示了BLOC-1-KIF13A-膜联蛋白A2分子网络的功能障碍是神经和色素性疾病病理生理学的基础。
