GSK-2606414

Seneca Valley virus (SVV), also known as Senecavirus A, a porcine pathogen that causes vesicular diseases, is prevalent in pig herds worldwide. SVV infection induces endoplasmic reticulum (ER) stress in PK-15 and BHK-21 cells, accompanied by activation of the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6) pathways, which in turn facilitates SVV replication. ER stress is associated with the regulation of Ca 2+ homeostasis and mitochondrial apoptosis. However, the precise role of Ca 2+ in SVV-induced apoptosis remains unclear. In this study, western blotting, flow cytometry, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) detection revealed that either ER stress or the PERK pathway is involved in the apoptosis of SVV-infected cells treated with specific inhibitors. Furthermore, SVV-mediated ER stress markedly contributed to the transfer of Ca 2+ from the ER to mitochondria. The subsequent increase in mitochondrial Ca 2+ content was accompanied by an increased number of ER membranes near the mitochondria. Finally, the inhibition of mitochondrial Ca 2+ overload, ER stress, and the PERK pathway substantially attenuated SVV-mediated mitochondrial dysfunction, as evidenced by analyzing mitochondrial membrane potential (MMP), mitochondrial permeability transition poremPTP, reactive oxygen speciesROS, and adenosine 5′-triphosphate ATP, and the levels of mitochondrial apoptosis. These findings demonstrate that SVV induces mitochondrial apoptosis, which is dependent on ER stress-mediated transmission of Ca 2+ from the ER to the mitochondria.

Viruses have developed multiple mechanisms to facilitate their proliferation or persistence through manipulating various organelles in cells. Seneca Valley virus (SVV), as a novel emerging pathogen associated with vesicular disease, is clinically and economically important infections that affect farm animals. Previously, we had confirmed that SVV-induced endoplasmic reticulum (ER) stress benefited for viral replication. Ca 2+ , as an intracellular signaling messenger mainly stored in the ER, is regulated by ER stress and then involved in apoptosis. However, the precise mechanism that Ca 2+ transfer induced by SVV infection triggered apoptosis remained unclear. Here, we found that SVV infection triggered the Ca 2+ transform from ER to mitochondria, resulting in mitochondrial dysfunction, and finally induced mitochondrial apoptosis. Our study shed light on a novel mechanism revealing how ER stress manipulates Ca 2+ homeostasis to induce mitochondrial apoptosis and regulate viral proliferation.

Melanocytes protect the body from ultraviolet radiation by synthesizing melanin. Tyrosinase, a key enzyme in melanin production, accumulates in the endoplasmic reticulum (ER) during melanin synthesis, potentially causing ER stress. However, regulating ER function for melanin synthesis has been less studied than controlling Tyrosinase activity.

This study investigates the regulatory mechanisms of melanin production, focusing on ER stress and the ER stress-induced response.

B16 mouse melanoma cells induced to undergo melanogenesis were treated with unfolded protein response (UPR) inhibitors or chemical chaperones, and their effects on melanogenesis were analyzed.

During melanogenesis in B16 cells stimulated by alpha-melanocyte-stimulating hormone (α-MSH), ER stress and UPR activation occurred, accompanied by increased Tyrosinase protein. Reducing IRE1 and ATF6 branch activity lowered melanin levels, while chemical chaperone treatment restored melanin production and increased Tyrosinase levels.

UPR activation, linked to elevated Tyrosinase levels, influences melanin production during melanogenesis. Modulating UPR can regulate melanin synthesis and provides a potential new approach for treating pigmentation disorders.