Mucolipin-2 localizes to the Arf6-associated pathway and regulates recycling of GPI-APs.
In mammals, the mucolipin family includes three members mucolipin-1, mucolipin-2, and mucolipin-3 (MCOLN1-3). While mutations in MCOLN1 and MCOLN3 have been associated with mucolipidosis type IV and the varitint-waddler mouse phenotype, respectively, little is known about the function and cellular distribution of MCOLN2. Here we show that MCOLN2 traffics via the Arf6-associated pathway and colocalizes with major histocompatibility protein class I (MHCI) and glycosylphosphatidylinositol-anchored proteins (GPI-APs), such as CD59 in both vesicles and long tubular structures. Expression of a constitutive active Arf6 mutant, or activation of endogenous Arf6 by transfection with EFA6 or treatment with aluminum fluoride, caused accumulation of MCOLN2 in enlarged vacuoles that also contain MHCI and CD59. In addition, overexpression of MCOLN2 promoted efficient activation of Arf6 in vivo, thus suggesting that MCOLN2 may have a role in the traffic of cargo through the Arf6-associated pathway. In support of this we found that overexpression of a MCOLN2 inactive mutant decreases recycling of CD59 to the plasma membrane. Therefore, our results indicate that MCOLN2 localizes to the Arf6-regulated pathway and regulates sorting of GPI-APs.
Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Claudia
C
Karacsonyi
Anitza San
AS
Miguel
Rosa
R
Puertollano
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D018957:CD59 Antigens / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D050051:Transient Receptor Potential Channels / Q000378:metabolism / Q000502:physiology*
D000089982:ADP-Ribosylation Factor 6; D018957:CD59 Antigens; D017261:Glycosylphosphatidylinositols; D015395:Histocompatibility Antigens Class I; C510641:Mcoln2 protein, human; D008565:Membrane Proteins; D050051:Transient Receptor Potential Channels; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse