The calcium channel mucolipin-3 is a novel regulator of trafficking along the endosomal pathway.
The varitint-waddler phenotype in mice is caused by gain-of-function mutations in mucolipin-3 (MCOLN3), a member of the mucolipin family of ion channels. These mice are characterized by defects in pigmentation, hearing loss and vestibular defects, suggesting that MCOLN3 might play a role in melanosome trafficking and hair cell maturation. Recent evidence has shown that MCOLN3 is a Ca(2+)-permeable channel and its activity is regulated by pH. Here we show that MCOLN3 primarily localizes to early and late endosomes in human epithelial cells. This distribution at the less acidic portions of the endocytic pathway is consistent with the reported inactivation of the channel by low pH. Furthermore, overexpression of MCOLN3 causes dramatic alterations in the endosomal pathway, including enlargement of Hrs-positive endosomes, delayed degradation of epidermal growth factor (EGF) and EGF receptor (EGFR) and defective autophagosome maturation, whereas depletion of endogenous MCOLN3 enhances EGFR degradation. Finally, we found that endosomal pH is higher in cells overexpressing MCOLN3 and propose a model in which Ca(2+) release from endosomes mediated by MCOLN3 might be important for efficient endosomal acidification. Therefore, MCOLN3 is a novel Ca(2+) channel that plays a crucial role in the regulation of cargo trafficking along the endosomal pathway.
Martina
Jose A
JA
Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Lelouvier
Benjamin
B
Puertollano
Rosa
R
D000818:Animals; D001343:Autophagy; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D010588:Phagosomes / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
C510642:MCOLN3 protein, human; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D050051:Transient Receptor Potential Channels; D025801:Ubiquitin; D066246:ErbB Receptors