Manganese-induced Trafficking and Turnover of the cis-Golgi Glycoprotein GPP130

Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
Molecular biology of the cell (Impact Factor: 4.47). 04/2010; 21(7):1282-92. DOI: 10.1091/mbc.E09-11-0985
Source: PubMed


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.

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Available from: Donald R Smith, Apr 02, 2015
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    • "Even if the second possibility is true, then the newly synthesized DAT protein which accumulates within the cell cannot be delivered to the cell surface thus, supporting our overall hypothesis that Mn alters DAT redistribution. This observation is consistent with previous reports demonstrating that Mn can alter the distribution of other membrane proteins (Mukhopadhyay et al., 2010; Wang et al., 2008). Once internalized, DAT can undergo ubiquitination and proteasomal degradation via a PKC-dependent pathway (Boudanova et al., 2008; Miranda et al., 2007). "
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    • "GPP130 also interacts with the COG subunit COG3P, and upon knockdown of this protein GPP130 is degraded after accumulating in COG complex-dependent vesicles, accompanied by blocked retrograde transport of Shiga toxin B (Zolov and Lupashin, 2005). Interestingly, GPP130 is degraded by treating cells with small amounts of manganese (Mn 2þ ) (Mukhopadhyay et al., 2010), a degradation leading to protection against Shiga toxicity by causing missorting of the toxin (Mukhopadhyay and Linstedt, 2012). This also provides a feasible explanation of past observations of manganeseinduced Shiga toxin protection (Sandvig and Brown, 1987). "
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