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Sequences in the cytoplasmic tail of SARS-CoV-2 Spike facilitate expression at the cell surface and syncytia formation

ABSTRACT: The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds the cell surface protein ACE2 to mediate fusion of the viral membrane with target cells1-4. S comprises a large external domain, a transmembrane domain (TMD) and a short cytoplasmic tail5,6. To elucidate the intracellular trafficking of S protein in host cells we applied proteomics to identify cellular factors that interact with its cytoplasmic tail. We confirm interactions with components of the COPI, COPII and SNX27/retromer vesicle coats, and with FERM domain actin regulators and the WIPI3 autophagy component. The interaction with COPII promotes efficient exit from the endoplasmic reticulum (ER), and although COPI-binding should retain S in the early Golgi system where viral budding occurs, the binding is weakened by a suboptimal histidine residue in the recognition motif. As a result, S leaks to the surface where it accumulates as it lacks an endocytosis motif of the type found in many other coronaviruses7-10. It is known that when at the surface S can direct cell:cell fusion leading to the formation of multinucleate syncytia7-9. Thus, the trafficking signals in the cytoplasmic tail of S protein indicate that syncytia formation is not an inadvertent by-product of infection but rather a key aspect of the replicative cycle of SARS-CoV-2 and potential cause of pathological symptoms.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Embryonic Cell, Kidney

DISEASE(S): Covid-19

SUBMITTER: Mark Skehel

LAB HEAD: Sean Munro

PROVIDER: PXD022215 | Pride | 2021-07-30

REPOSITORIES: Pride

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Project description:This experiment was conducted to identify mRNA transcripts alteration in liver of Ern1 liver specific knockout mice. The following abstract from the submitted manuscript describes the major findings of this work. The IRE1a-XBP1s axis regulates the COPII-mediated secretory program in response to nutrient availability. Lin Liu, Jie Cai, Xijun Liang, Qian Zhou, Huimin Wang, Chenyun Ding, Yuangang Zhu, Liwei Xiao, Tingting Fu, Zhisheng Xu, Jing Liu, Yujing Yin, Lei Fang, Bin Xue, Yan Wang, Aibin He, Yong Liu, Xiao-Wei Chen, and Zhenji Gan The cytoplasmic coat protein complex-II (COPII) is an evolutionarily conserved machinery that is essential for efficient trafficking of protein and lipid cargos. How the COPII machinery is regulated to meet the metabolic demand in response to alterations of nutritional state remains largely unexplored, however. Here, we show that dynamic changes of COPII-mediated secretion parallel the activation of XBP1s, the critical transcription factor in handling cellular ER stress, in both live cells and mouse liver upon physiological fluctuations of nutrient availability. Using live-cell imaging approaches, we demonstrate that XBP1s is sufficient to promote COPII-dependent secretion, mediating the nutrient stimulatory effects. ChIP-seq and RNA-seq analyses reveal that nutritional signals induce dynamic XBP1s occupancy of promoters of COPII secretion-related genes, thereby driving COPII-directed secretory process. Liver-specific disruption of the IRE1a-XBP1s signaling branch results in diminished COPII-mediated secretion. Reactivation of XBP1s in mice lacking hepatic IRE1a restores COPII-mediated lipoprotein secretion, and reverses the fatty liver and hypolipidemia phenotypes. Thus, our results demonstrate a previously unappreciated mechanism in the metabolic control of liver protein and lipid secretion: the IRE1a-XBP1s axis functions as a nutrient-sensing regulatory nexus that integrates nutritional states and the COPII secretory program.

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Sequences in the cytoplasmic tail of SARS-CoV-2 Spike facilitate expression at the cell surface and syncytia formation

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