Abstract
Protein trafficking between the endoplasmic reticulum (ER) and Golgi apparatus is central to cellular homeostasis. ER export signals are utilized by a subset of proteins to rapidly exit the ER by direct uptake into COPII vesicles for transport to the Golgi. Norwalk virus nonstructural protein p22 contains a YXΦESDG motif that mimics a di-acidic ER export signal in both sequence and function. However, unlike normal ER export signals, the ER export signal mimic of p22 is necessary for apparent inhibition of normal COPII vesicle trafficking, which leads to Golgi disassembly and antagonism of Golgi-dependent cellular protein secretion. This is the first reported function for p22. Disassembly of the Golgi apparatus was also observed in cells replicating Norwalk virus, which may contribute to pathogenesis by interfering with cellular processes that are dependent on an intact secretory pathway. These results indicate that the ER export signal mimic is critical to the antagonistic function of p22, shown herein to be a novel antagonist of ER/Golgi trafficking. This unique and well-conserved human norovirus motif is therefore an appealing target for antiviral drug development.
Highlights
Maintenance of cellular homeostasis is directly dependent on the proper functioning of the Golgi apparatus, which is central to lipid trafficking and protein secretion
Due to Golgi rearrangements observed during feline calicivirus (FCV) [24] and murine norovirus (MNV) [25] replication, we first determined if the Golgi is morphologically changed during human Norwalk virus (NV) replication
The major new findings of this study can be summarized as follows: 1) independent expression of p22 disassembles the Golgi, which occurs during NV replication, and inhibits cellular protein secretion; 2) subcellular localization of p22 depends on a motif that mimics a cellular endoplasmic reticulum (ER) export signal in both sequence and function, which we have named a MERES motif; and 3) p22 depends on the MERES motif likely to antagonize COPII vesicle trafficking, resulting in Golgi disassembly and an inhibition of cellular protein secretion
Summary
Maintenance of cellular homeostasis is directly dependent on the proper functioning of the Golgi apparatus, which is central to lipid trafficking and protein secretion. Protein trafficking from the endoplasmic reticulum (ER) to the Golgi is mediated by vesicles coated in COPII protein complexes, whereas the retrograde Golgi-toER pathway is mediated by COPI-coated vesicles [1]. Upon export from the ER at ER exit sites (ERES), cellular proteins accumulate and traffic into budding COPII vesicles, which are minimally composed of the GTPase Sar and heteromeric complexes of Sec13/31 and Sec23/24 [2,3]. Export of proteins from the ER and subsequent trafficking of COPII vesicles to the Golgi is mediated by a number of cellular factors, and proteins of both cellular and microbial origin are known to antagonize this pathway
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