Manganese-induced trafficking and turnover of the cis-Golgi glycoprotein GPP130.
Manganese is an essential element that is also neurotoxic at elevated exposure. However, mechanisms regulating Mn homeostasis in mammalian cells are largely unknown. Because increases in cytosolic Mn induce rapid changes in the localization of proteins involved in regulating intracellular Mn concentrations in yeast, we were intrigued to discover that low concentrations of extracellular Mn induced rapid redistribution of the mammalian cis-Golgi glycoprotein Golgi phosphoprotein of 130 kDa (GPP130) to multivesicular bodies. GPP130 was subsequently degraded in lysosomes. The Mn-induced trafficking of GPP130 occurred from the Golgi via a Rab-7-dependent pathway and did not require its transit through the plasma membrane or early endosomes. Although the cytoplasmic domain of GPP130 was dispensable for its ability to respond to Mn, its lumenal stem domain was required and it had to be targeted to the cis-Golgi for the Mn response to occur. Remarkably, the stem domain was sufficient to confer Mn sensitivity to another cis-Golgi protein. Our results identify the stem domain of GPP130 as a novel Mn sensor in the Golgi lumen of mammalian cells.
Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
Somshuvra
S
Mukhopadhyay
Collin
C
Bachert
Donald R
DR
Smith
Adam D
AD
Linstedt
D000818:Animals; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D004705:Endocytosis; D004815:Epidermal Growth Factor / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008247:Lysosomes / Q000378:metabolism; D008345:Manganese / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence / Q000379:methods; D017434:Protein Structure, Tertiary; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
C107340:GOLIM4 protein, human; C410824:GOLM1 protein, human; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; D000090802:rab7 GTP-Binding Proteins; D008345:Manganese; D004815:Epidermal Growth Factor; D020691:rab GTP-Binding Proteins