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轮状病毒钙调控表现为细胞质和内质网中动态钙信号。

Rotavirus Calcium Dysregulation Manifests as Dynamic Calcium Signaling in the Cytoplasm and Endoplasmic Reticulum.

机构信息

Alkek Center for Metagenomic and Microbiome Research, Department of Molecular Virology and Microbiology, Houston, USA.

Department of Biology, Indiana University, Bloomington, IN, 47405, USA.

出版信息

Sci Rep. 2019 Jul 25;9(1):10822. doi: 10.1038/s41598-019-46856-8.

DOI:10.1038/s41598-019-46856-8
PMID:31346185
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6658527/
Abstract

Like many viruses, rotavirus (RV) dysregulates calcium homeostasis by elevating cytosolic calcium ([Ca]cyt) and decreasing endoplasmic reticulum (ER) stores. While an overall, monophasic increase in [Ca]cyt during RV infection has been shown, the nature of the RV-induced aberrant calcium signals and how they manifest over time at the single-cell level have not been characterized. Thus, we generated cell lines and human intestinal enteroids (HIEs) stably expressing cytosolic and/or ER-targeted genetically-encoded calcium indicators to characterize calcium signaling throughout RV infection by time-lapse imaging. We found that RV induces highly dynamic [Ca]cyt signaling that manifest as hundreds of discrete [Ca]cyt spikes, which increase during peak infection. Knockdown of nonstructural protein 4 (NSP4) attenuates the [Ca]cyt spikes, consistent with its role in dysregulating calcium homeostasis. RV-induced [Ca]cyt spikes were primarily from ER calcium release and were attenuated by inhibiting the store-operated calcium entry (SOCE) channel Orai1. RV-infected HIEs also exhibited prominent [Ca]cyt spikes that were attenuated by inhibiting SOCE, underlining the relevance of these [Ca]cyt spikes to gastrointestinal physiology and role of SOCE in RV pathophysiology. Thus, our discovery that RV increases [Ca]cyt by dynamic calcium signaling, establishes a new, paradigm-shifting understanding of the spatial and temporal complexity of virus-induced calcium signaling.

摘要

与许多病毒一样，轮状病毒（RV）通过升高细胞质钙（[Ca] cyt）和减少内质网（ER）储存来调节钙稳态。虽然已经显示 RV 感染过程中[Ca] cyt总体呈单相增加，但 RV 诱导的异常钙信号的性质以及它们如何随时间在单细胞水平上表现尚未得到表征。因此，我们生成了稳定表达细胞质和/或 ER 靶向遗传编码钙指示剂的细胞系和人肠类器官（HIE），通过延时成像来表征 RV 感染过程中的钙信号。我们发现，RV 诱导高度动态的[Ca] cyt 信号，表现为数百个离散的[Ca] cyt 峰，在感染高峰期增加。非结构蛋白 4（NSP4）的敲低减弱了[Ca] cyt 峰，与其在调节钙稳态中的作用一致。RV 诱导的[Ca] cyt 峰主要来自 ER 钙释放，并通过抑制储存操作钙进入（SOCE）通道 Orai1 而减弱。RV 感染的 HIE 也表现出明显的[Ca] cyt 峰，通过抑制 SOCE 减弱，突出了这些[Ca] cyt 峰与胃肠道生理学的相关性以及 SOCE 在 RV 病理生理学中的作用。因此，我们发现 RV 通过动态钙信号增加[Ca] cyt，这为病毒诱导的钙信号的时空复杂性建立了一种新的、具有范式转变意义的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/01575e639fc2/41598_2019_46856_Fig11_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/01575e639fc2/41598_2019_46856_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/46ad3787dcca/41598_2019_46856_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/338ab16a7ed1/41598_2019_46856_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/abdcf0f26c42/41598_2019_46856_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/716cc0fd52dd/41598_2019_46856_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/f0596076afdc/41598_2019_46856_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/722ca12f228b/41598_2019_46856_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/65f513cca7fa/41598_2019_46856_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/51a57d5a4ee0/41598_2019_46856_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/4201ab095d5b/41598_2019_46856_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/0c351b4b94d5/41598_2019_46856_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74a5/6658527/01575e639fc2/41598_2019_46856_Fig11_HTML.jpg

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