Induced oligomerization targets Golgi proteins for degradation in lysosomes

Abstract

Oligomerization or homotypic clustering diverts Golgi membrane proteins into the canonical GGA1/clathrin-dependent Golgi-to-lysosome pathway revealing the presence of cellular quality control that could be useful for therapies designed to down-regulate specific proteins in the secretory pathway.

Protein quality control in the secretory pathway

“…Sortilin is a Vps10 orthologue that resides primarily in the Golgi and plasma membrane and mediates lysosomal cargo sorting (Nielsen et al, 1999(Nielsen et al, , 2001Lefrancois et al, 2003;Amengual et al, 2018). Similar to its yeast counterpart, sortilin also regulates the lysosomal sorting of misfolded proteins, such as aggregated GPP130, which is induced by manganese (Tewari et al, 2015;Venkat and Linstedt, 2017). Interestingly, while oligomerization/aggregation is sufficient to trigger lysosomal degradation, trafficking is sortilin independent, suggesting that protein aggregation is necessary, but not sufficient, for sortilin-mediated sorting.…”

ZIP14 is degraded in response to manganese exposure

“…The Golgi apparatus appears to play an important role in cellular Mn homeostasis and effects on its function often occur over the Mn concentration range used for our studies (Carmona et al 2019;Houdou et al 2019). In fact, previous studies examining Mnregulated proteins included treatments of cells with 1-500 lM Mn over time courses ranging from 1 to 24 h (Masuda et al 2013;Mukhopadhyay et al 2010;Potelle et al 2017;Tewari et al 2015;Towler et al 2000). For example, treatment of cells with 500 lM MnCl 2 induces rapid redistribution and lysosomal degradation of the Mn sensor protein GPP130 (Mukhopadhyay et al 2010).…”

Manganese-induced trafficking and turnover of GPP130 is mediated by sortilin

“…, 2010 ). Redistribution is via the canonical TGN-to-lysosome pathway as it requires the clathrin vesicle coat complex and its Golgi-localizing γ-adaptin homologous ARF-interacting protein 1 (GGA1) adaptor ( Tewari et al. , 2015 ).…”

“…Rather than being unique to GPP130, oligomerization may be a general trigger of Golgi protein exit and lysosomal degradation, possibly used for Golgi quality control ( Tewari et al. , 2015 ).…”

“…, 2014 ). Indeed, the placement of an array of self-interacting FM domains on the lumenal domain of a number of Golgi proteins causes their oligomerization-induced degradation in lysosomes ( Tewari et al. , 2015 ).…”