Dysregulated Arl1, a regulator of post-Golgi vesicle tethering, can inhibit endosomal transport and cell proliferation in yeast

Abstract

The yeast protein Gcs1 is a GTPase-activating protein (GAP) for Arf and Arl1 G-proteins that regulate distinct steps of vesicular transport. Absence of a GAP-independent function of Gcs1 results in dysregulated Arl1, which in turn impairs cell growth and endosomal transport. Impairing vesicle-tethering pathways removes dysregulated Arl1 and alleviates these defects.

Competition between the golgin Imh1p and the Gcs1p GAP stabilizes activated Arl1p at the late-Golgi

“…However, physical interaction between Imh1p and Ypt6p has not been observed to date. Although recent studies showed that Arl1p and Imh1p were no longer localized to the Golgi in ypt6D cells (Benjamin et al, 2011), whether Ypt6p is involved in the Arl1p-Imh1p pathway through a transit interaction with Imh1p or indirect effect remains to be determined.…”

The yeast cell wall integrity pathway signals from recycling endosomes upon elimination of phosphatidylinositol (4,5)-bisphosphate by mammalian phosphatidylinositol 3-kinase

“…In yeast, mutants affected in Golgi Arf GTPase regulation present a TGN fragmentation, as well as FM4-64 endocytic and Snc1 recycling defects [25,67,68]. Thus, it is feasible that PtdIns(4,5)P 2 regulates activity of Arf/Rab GTPases.…”

Multiple activities of Arl1 GTPase in the trans-Golgi network

“…In mammalian cells, these functions affect a wide range of fundamental cellular processes, including cell polarity (Lock et al, 2005), innate immunity (Bremond et al, 2009;Lieu et al, 2008;Murray and Stow, 2014;Stanley et al, 2012), lipid droplet and chylomicron formation (Hesse et al, 2013;Jaschke et al, 2012), as well as the secretion of insulin (Gehart et al, 2012), chromogranin A (CruzGarcia et al, 2013) and matrix metalloproteinases (MMPs) (Eiseler et al, 2016). In yeast, Arl1 and its effectors are also involved in numerous functions, such as maintenance of cell wall integrity (Liu et al, 2006), ion homeostasis (Marešová and Sychrová, 2010;Munson et al, 2004;Rosenwald et al, 2002), tolerance to stress factors (Jaime et al, 2012;Marešova et al, 2012;Yang and Rosenwald, 2016), regulation of cell proliferation (Benjamin et al, 2011), the unfolded protein response (UPR) (Hsu et al, 2016) and also in the ability of yeast to cause disease (Labbaoui et al, 2017). In addition, these factors regulate the quality control of the endoplasmic reticulum (ER) (Lee et al, 2011), tissue development (Eisman et al, 2006;Torres et al, 2014) and neuronal growth in Drosophila (Chang et al, 2015), and control cell viability in parasites (Price et al, 2005).…”

“…Furthermore, the Arl1-deletion mutant shows defects in cell wall integrity (Liu et al, 2006) and is more sensitive to salts (KCl, NaCl and LiCl), high temperatures, increased pH, hygromycin B and chitosan oligosaccharide than cells that possess the wild-type Arl1 (Jaime et al, 2012;Marešová and Sychrová, 2010;Marešová et al, 2012), supporting a role for Arl1 in tolerance to extracellular stress and/or stimulation. Arl1 also functions in cell proliferation, as demonstrated by the observation that dysregulation of active yeast Arl1 in response to a lack of its GAP Gcs1 prevents cell growth and impairs endosomal transport at low temperatures (Benjamin et al, 2011). Arl1 also shows synthetic lethality and physical interactions with Vps53, one of the subunits of the Golgi-associated retrograde protein (GARP) complex (Panic et al, 2003b;Tong et al, 2004), indicating that at least some functions of the GARP complex in endosomal TGN trafficking overlap with those of Arl1.…”