Unfolded protein response regulates yeast small GTPase Arl1p activation at late Golgi via phosphorylation of Arf GEF Syt1p

Abstract

ADP ribosylation factor (Arf) GTPases are key regulators of membrane traffic at the Golgi complex. In yeast, Arf guanine nucleotide-exchange factor (GEF) Syt1p activates Arf-like protein Arl1p, which was accompanied by accumulation of golgin Imh1p at late Golgi, but whether and how this function of Syt1p is regulated remains unclear. Here, we report that the inositol-requiring kinase 1 (Ire1p)-mediated unfolded protein response (UPR) modulated Arl1p activation at late Golgi. Arl1p activation was dependent on both kinase and endo-RNase activities of Ire1p. Moreover, constitutively active transcription factor Hac1p restored the Golgi localization of Arl1p and Imh1p in IRE1-deleted cells. Elucidating the mechanism of Ire1p–Hac1p axis actions, we found that it regulated phosphorylation of Syt1p, which enhances Arl1p activation, recruitment of Imh1p to the Golgi, and Syt1p interaction with Arl1p. Consistent with these findings, the induction of UPR by tunicamycin treatment increases phosphorylation of Syt1p, resulting in Arl1p activation. Thus, these findings clarify how the UPR influences the roles of Syt1p, Arl1p, and Imh1p in Golgi transport.

Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain

“…In some settings, the Golgi quality control contributes to UPR by capturing misfolded proteins that emanate from the ER, diverting them for lysosomal degradation (36). In fact, it is known that cleaved ATF6 induces ERGIC53 expression (37) and its redistribution so that it is closer to the cis-Golgi (38), both of which are features present in cells expressing Ala92-D2 HY .…”

Multiple activities of Arl1 GTPase in the trans-Golgi network

“…Recently, we have shown that Ire1−Hac1 signaling regulates Arl1 activity by controlling Syt1 phosphorylation (Fig. 2) (Hsu et al, 2016). Ire1 is a kinase/endoribonuclease that localizes to the ER membrane and is activated by ER stress (Kimata and Kohno, 2011;Parmar and Schröder, 2012).…”

“…Genetic alterations of Arl1 as well as its effectors were used to characterize developmental and physiological phenotypes (summarized in Fig. 1) (Chang et al, 2015;Cruz-Garcia et al, 2013;Eiseler et al, 2016;Gehart et al, 2012;Hesse et al, 2013;Hsu et al, 2016;Labbaoui et al, 2017;Lieu et al, 2008;Liu et al, 2006;Lock et al, 2005;Marešová and Sychrová, 2010;Marešová et al, 2012;Murray and Stow, 2014;Price et al, 2005;Torres et al, 2014;Yang and Rosenwald, 2016). 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 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).…”

“…As shown in our recent study, ER stress induces the phosphorylation of Syt1 at S416 through the Ire1-Hac1 signaling pathway, which then promotes interaction of Syt1 with Arl1 in the late Golgi, resulting in Arl1 activation and Golgi targeting of Imh1. Importantly, both phosphorylation of Syt1 at S416 and Arl1 activity are increased upon treatment with the UPR inducer tunicamycin (Hsu et al, 2016). A better understanding of how the UPR influences the role of the Syt1-Arl1-Imh1 cascade in Golgi transport could also provide important mechanistic insights into how the Golgi contributes to mitigating proteotoxic stress from the ER.…”