The IRE1α-XBP1 arm of the unfolded protein response is a host factor activated in SARS-CoV-2 infection

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1870; no. 5; p. 167193
• Main Authors: Fernández, Jose Javier, Marín, Arturo, Rosales, Romel, Penrice-Randal, Rebekah, Mlcochova, Petra, Alvarez, Yolanda, Villalón-Letelier, Fernando, Yildiz, Soner, Pérez, Enrique, Rathnasinghe, Raveen, Cupic, Anastasija, Kehrer, Thomas, Uccellini, Melissa B., Alonso, Sara, Martínez, Fernando, McGovern, Briana Lynn, Clark, Jordan J., Sharma, Parul, Bayón, Yolanda, Alonso, Andrés, Albrecht, Randy A., White, Kris M., Schotsaert, Michael, Miorin, Lisa, Stewart, James P., Hiscox, Julian A., Gupta, Ravindra K., Irigoyen, Nerea, García-Sastre, Adolfo, Crespo, Mariano Sánchez, Fernández, Nieves
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2024
• Subjects: Animals; COVID-19; COVID-19 - immunology; COVID-19 - metabolism; COVID-19 - pathology; COVID-19 - virology; Cytokines; Cytokines - metabolism; Endoribonucleases - genetics; Endoribonucleases - metabolism; Female; Fluvoxamine; Humans; Mesocricetus; Mice; Mice, Inbred C57BL; Pneumonia; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; SARS-CoV-2 - metabolism; Signal Transduction; TLR; Transcription factors; Unfolded Protein Response; Variants of concern; Viral sepsis; Virus Replication; X-Box Binding Protein 1 - genetics; X-Box Binding Protein 1 - metabolism; COVID-19; Viral sepsis; Pneumonia; Transcription factors; Cytokines; Variants of concern; TLR; Fluvoxamine; Unfolded protein response
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167193

SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state involves the activation of the innate immune response by viral patterns and coincides with the biosynthesis of the biomass required for viral replication, which may overwhelm the capacity of the endoplasmic reticulum and drive the unfolded protein response (UPR). The UPR is a signal transduction pathway composed of three branches that is initiated by a set of sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). These sensors control adaptive processes, including the transcriptional regulation of proinflammatory cytokines. Based on this background, the role of the UPR in SARS-CoV-2 replication and the ensuing inflammatory response was investigated using in vivo and in vitro models of infection. Mice and Syrian hamsters infected with SARS-CoV-2 showed a sole activation of the Ire1α-Xbp1 arm of the UPR associated with a robust production of proinflammatory cytokines. Human lung epithelial cells showed the dependence of viral replication on the expression of UPR-target proteins branching on the IRE1α-XBP1 arm and to a lower extent on the PERK route. Likewise, activation of the IRE1α-XBP1 branch by Spike (S) proteins from different variants of concern was a uniform finding. These results show that the IRE1α-XBP1 system enhances viral replication and cytokine expression and may represent a potential therapeutic target in SARS-CoV-2 severe pneumonia. [Display omitted] •SARS-CoV-2 infection of mice and Syrian hamsters activates the Ire1α-Xbp1 arm of UPR.•Ire1α-Xbp1 arm activity is associated with proinflammatory cytokine production.•SARS-CoV-2 leverages the Ire1α-Xbp1 arm for replication in lung epithelial cells.•The IRE1α-XBP1 arm is activated by Spike proteins from different variants of concern.