Abstract

Calcium (Ca 2+ ), a ubiquitous second messenger, plays a crucial role in many cellular functions. Viruses often hijack Ca 2+ signaling to facilitate viral processes such as entry, replication, assembly, and egress. Here, we report that infection by the swine arterivirus, porcine reproductive and respiratory syndrome virus (PRRSV), induces dysregulated Ca 2+ homeostasis, subsequently activating calmodulin-dependent protein kinase-II (CaMKII) mediated autophagy, and thus fueling viral replication. Mechanically, PRRSV infection induces endoplasmic reticulum (ER) stress and forms a closed ER–plasma membrane (PM) contacts, resulting the opening of store operated calcium entry (SOCE) channel and causing the ER to take up extracellular Ca 2+ , which is then released into the cytoplasm by inositol trisphosphate receptor (IP3R) channel. Importantly, pharmacological inhibition of ER stress or CaMKII mediated autophagy blocks PRRSV replication. Notably, we show that PRRSV protein Nsp2 plays a dominant role in the PRRSV induced ER stress and autophagy, interacting with stromal interaction molecule 1 (STIM1) and the 78 kDa glucose-regulated protein 78 (GRP78). The interplay between PRRSV and cellular calcium signaling provides a novel potential approach to develop antivirals and therapeutics for the disease outbreaks. Porcine reproductive and respiratory syndrome virus (PRRSV) infection results in a serious swine disease and causes a severe economic threat to the global swine industry. However, commercial vaccines do not provide satisfactory protection against PRRSV due to its genetic variation. Well understanding the mechanism of PRRSV replication is helpful to develop the effective strategies to control the disease. Calcium signaling has been reported to play an important role in the life cycles of viruses. In this study, we describe the picture that PRRSV infection induces