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The Murine Cytomegalovirus Immunoevasin Gp40 Binds MHC

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The Murine Cytomegalovirus Immunoevasin Gp40 Binds MHC © 2016. Published by The Company of Biologists Ltd | Journal of Cell Science (2016) 129, 219-227 doi:10.1242/jcs.175620 RESEARCH ARTICLE The murine cytomegalovirus immunoevasin gp40 binds MHC class I molecules to retain them in the early secretory pathway Linda Janßen1, Venkat Raman Ramnarayan1, Mohamed Aboelmagd1, Maro Iliopoulou1, Zeynep Hein1, Irina Majoul2, Susanne Fritzsche1, Anne Halenius3 and Sebastian Springer1,* ABSTRACT ERGIC or cis-Golgi, and we demonstrate that a sequence in the In the presence of the murine cytomegalovirus (mCMV) gp40 (m152) linker between the folded lumenal domain of gp40 and the protein, murine major histocompatibility complex (MHC) class I transmembrane sequence is required for this retention. molecules do not reach the cell surface but are retained in an early compartment of the secretory pathway. We find that gp40 does not RESULTS impair the folding or high-affinity peptide binding of the class I Gp40 retains MHC class I in the early secretory pathway molecules but binds to them, leading to their retention in the To assess the effect of gp40 on murine class I molecules, we m152 endoplasmic reticulum (ER), the ER-Golgi intermediate compartment expressed in K41 cells (murine fibroblasts) by lentiviral (ERGIC) and the cis-Golgi, most likely by retrieval from the cis-Golgi to transduction. The surface levels of the endogenous class I allotypes b b b b the ER. We identify a sequence in gp40 that is required for both its own H-2D (D ) and H-2K (K ) were reduced to background levels in retention in the early secretory pathway and for that of class I most cells, as observed by flow cytometry with the allotype-specific β b molecules. beta-2 microglobulin ( 2m)-dependent antibodies B22.249 (for D ) and Y3 (for Kb) (Fig. 1A). Kb, but not Db, was fully resistant to gp40 KEY WORDS: ERGIC and cis-Golgi retention, Antigen presentation, in some cells (arrow), especially in confluent cultures, and there was Early secretory pathway, Immune evasion, Murine cytomegalovirus no evidence of intermediate retention phenotypes. We conclude that whereas gp40-mediated retention of class I molecules can be highly INTRODUCTION effective, it varies between class I allotypes and growth conditions. To escape from destruction by the cellular adaptive immune system, To find the intracellular steady-state location of the gp40-retained viruses inhibit almost every step of major histocompatibility class I, we performed fluorescence microscopy with the same complex (MHC)-class-I-mediated antigen presentation (Ambagala antibodies, and we also stained for gp40 with an antibody against a et al., 2005). Herpesviruses encode multiple interfering proteins C-terminal hemagglutinin (HA) tag (Fig. 1B,C; Fig. S1). Gp40 was (immunoevasins) (Basta and Bennink, 2003). The glycoprotein observed in a compact juxtanuclear location that colocalized well 40 kDa (gp40) of the murine cytomegalovirus (mCMV), encoded with the ERGIC-53 (also known as LMAN1) marker (Fig. 1C, top by the m152 gene, was the first inhibitor of MHC-class-I-mediated row) and with the Golgi marker GM130 (also known as GOLGA2) antigen presentation and natural killer cell function to be described in (Fig. S2). Kb was found in the same location (Fig. 1B, top row, CMV (Krmpotićet al., 2002; Lu et al., 2006). Gp40 inhibits the Fig. 1C, center row; Fig. S1). In some cells (∼30%), Db localized transport of peptide-loaded class I molecules (proteins) to the cell exclusively to the same juxtanuclear region (Fig. 1B, bottom row; surface and retains them in the early secretory pathway, but its Fig. S1), but in the majority of cells, Db exhibited, in addition, a molecular mechanism of action is still unknown (Pinto and spread-out reticular pattern reminiscent of the ER (Fig. 1B, center Hill, 2005). Earlier investigations have shown that gp40-retained row, Fig. 1C, bottom row, Fig. 1D; Fig. S1). In agreement with class I molecules are bound to high-affinity peptide but fail earlier data for H-2Kd (Ziegler et al., 1997), we conclude that Db and to proceed beyond the ER-Golgi intermediate compartment Kb are indeed retained in an intracellular compartment where they (ERGIC). In contrast, gp40 itself has been shown to progress to colocalize with gp40, and we also find that the exact steady-state the lysosomes for degradation. The authors found an interaction of subcellular location of a gp40-retained class I molecule depends on gp40 with calnexin but not with class I molecules (Ziegler et al., the allotype (Kavanagh et al., 2001). 2000, 1997). To understand the influence of gp40 on the kinetics of class I Gp40 also retains the class-I-related stress marker RAE-1. transport from the ER to the Golgi, we next performed radiolabeling Recently, a crystal structure of gp40 in complex with RAE-1 has and pulse-chase experiments with endoglycosidase F1 digests been published (Zhi et al., 2010). This has prompted us to re- (EndoF1; see Materials and Methods). In wild-type cells, Db and Kb examine the question of gp40–class-I interaction. We show here glycans become resistant to digestion with EndoF1 in the medial that, indeed, gp40 binds to class I molecules to retain them in Golgi due to the action of mannosidase II. When they reach the the early secretory pathway, most likely by retrieval from the trans-Golgi, further carbohydrates including sialic acids are added; this sialylation results in an upward shift of the EndoF1-resistant 1 band on SDS-PAGE gels (Fritzsche and Springer, 2013). In gp40- Department of Life Sciences and Chemistry, Jacobs University Bremen, b 28759 Bremen, Germany. 2Institute of Biology, Center for Structural and Cell Biology expressing cells, D showed no sialylation after 2 h of chase in Medicine, University of Lübeck, 23562 Lübeck, Germany. 3Institute of Virology, (Fig. 1E, bottom row); thus, it had not passed the trans-Golgi. University Medical Center, University of Freiburg, 79104 Freiburg, Germany. In contrast, Kb showed a small amount of EndoF1 resistance *Author for correspondence ([email protected]) and sialylation (Fig. 1E, second row, sia). This agrees with the above observation that in the presence of gp40, Kb can still reach the Received 10 June 2015; Accepted 26 October 2015 surface in some cells (Fig. 1A, arrow). Journal of Cell Science 219 RESEARCH ARTICLE Journal of Cell Science (2016) 129, 219-227 doi:10.1242/jcs.175620 Fig. 1. See next page for legend. Remarkably, at the 2-h time point, both Db and Kb acquired partial gp40-free control samples, where Db and Kb progressed directly (incomplete) EndoF1 resistance, visible as two (Kb) or three (Db) from the EndoF1-sensitive form to the fully EndoF1-resistant and intermediate bands between the EndoF1-resistant and -sensitive sialylated form. At longer chase times of up to 16 h, the partially forms (Fig. 1E, arrowheads), corresponding to the number of EndoF1-resistant forms of Db and Kb persisted (Fig. 1F, b glycosylation sites for each allotype. This was never seen in the arrowheads), and sialylation still did not occur (D ), or only for a Journal of Cell Science 220 RESEARCH ARTICLE Journal of Cell Science (2016) 129, 219-227 doi:10.1242/jcs.175620 Fig. 1. Gp40 retains MHC class I molecules. (A) Gp40 abolishes class I was also visible for a variant of gp40 with a C-terminal cytosolic surface expression. Gp40 was expressed in K41 cells, and surface expression KKSQ sequence for ER retention (Fig. S3C). Thus, in our system, at of endogenous class I was determined by cell surface staining with B22.249 b b least some gp40 is retained in a pre-medial-Golgi compartment, most (D ) and Y3 (K ) and flow cytometry. Gray shading, a second antibody control; – solid line, empty vector control; dashed line, gp40-expressing cells. One likely in an ER Golgi cycle, just like the class I molecules that it b representative experiment out of five is shown. (B) In the presence of gp40, Kb retains. Interestingly, the gp40-KKSQ variant retained both D and b and Db localize to juxtanuclear compartments, and Db additionally localizes to K very efficiently, which suggests that gp40 does not need to the ER. Gp40-expressing K41 cells were fixed, permeabilized and stained with progress beyond the cis-Golgi to be effective (Fig. S3D). FITC-conjugated anti-HA antibody (gp40), and with B22 (Db)orY3(Kb) and Cy3-conjugated secondary antibody. (C) To show ERGIC localization, cells Gp40 does not impair class I maturation or peptide binding were stained with Cy3-conjugated ERGIC-53 antiserum and either with FITC- conjugated anti-HA antibody or Y3 followed by Alexa-Fluor-488-conjugated Many viral proteins interfere with class I synthesis and folding or secondary antibody. More images are shown in Fig. S1 and are available from with peptide loading onto class I molecules, for example by the authors. Scale bars: 20 µm. (D) For quantification of the colocalization inhibiting or removing TAP (Loch and Tampe, 2005; Momburg between gp40 and Db and Kb, individual cells were examined by eye and and Hengel, 2002). Given that our results suggested that gp40 acts assigned to one of three categories, according to the colocalization of the in the early secretory pathway, we first asked whether it inhibits class I molecule with gp40: +, total colocalization with gp40, no ER localization; class I folding and peptide binding. We applied a 5-min radioactive − o, mostly colocalization with gp40, little to some ER localization; , little pulse and followed the folding of the class I heavy chains by colocalization with gp40, mostly ER localization. For the quantification, β additional microscopic images were used, which are not shown. Light gray immunoprecipitating with 2m-dependent antibodies at different b b bars, Db; dark gray bars, Kb.(E–G) Pulse-chase analysis of class I molecules chase times and quantifying total D or K .
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