Transmission of unfolded protein response-a regulator of disease progression, severity, and spread in virus infections

Abstract

The unfolded protein response (UPR) is a cell-autonomous stress response aimed at restoring homeostasis due to the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Viruses often hijack the host cell machinery, leading to an accumulation of misfolded proteins in the ER. The cell-autonomous UPR is the immediate response of an infected cell to this stress, aiming to restore normal function by halting protein translation, degrading misfolded proteins, and activating signaling pathways that increase the production of molecular chaperones. The cell-non-autonomous UPR involves the spreading of UPR signals from initially stressed cells to neighboring unstressed cells that lack the stressor. Though viruses are known modulators of cell-autonomous UPR, recent advancements have highlighted that cell-non-autonomous UPR plays a critical role in elucidating how local infections cause systemic effects, thereby contributing to disease symptoms and progression. Additionally, by utilizing cell-non-autonomous UPR, viruses have devised novel strategies to establish a pro-viral state, promoting virus spread. This review discusses examples that have broadened the understanding of the role of UPR in virus infections and disease progression by looking beyond cell-autonomous to non-autonomous processes and mechanistic details of the inducers, spreaders, and receivers of UPR signals.

Keywords: cell-non-autonomous UPR; disease progression; pro-viral state; unfolded protein response (UPR); virus infections.

Fig 1

Cell-autonomous, non-autonomous UPR, and UPR signal heterogeneity—UPR signaling controls the fate of cell survival and death in primary UPR-initiating cells (yellow) and neighboring bystander cells (blue) via cell intrinsic and extrinsic factors and processes, respectively. Cell intrinsic factors are well characterized, but extrinsic factors are preliminary and speculative. The scale at the bottom of the figure indicates whether the cell-non-autonomous UPR acts in short distance (within tissue or organ) or long distance (across organs). Short-distance paracrine signaling in neighboring cells of the tissue occurs via secreted biomolecules. Long-distance endocrine signaling occurs across organs via bloodstream. The color scheme shows whether the UPR is induced in a cell via cell-autonomous (yellow) or non-autonomous (blue), whereas the intensity of the color shows whether UPR signaling is high or low. The differential UPR signaling in the producer and bystander cells of the same tissue or across organs in an organism signifies the heterogeneity of UPR signaling in a system.

Fig 2

Cell-non-autonomous UPR in virus spread and pathogenicity—(A)Cell-non-autonomous UPR signaling promoting cardiac myopathy in CVB3-infected mice by transmission of UPR via unknown biomolecules from infected myocardium to wandering macrophages. The cell-autonomous UPR (yellow) activation in CVB3-infected myocardium promoted the release of unknown cell extrinsic factors that activated cell-non-autonomous UPR (blue) in wandering macrophages. This leads to pro-inflammatory cytokine secretion further activating the cell non-autonomous UPR in the neighboring healthy myocardium inducing cell death (cardiac myopathy) (65). (B)Cell-non-autonomous UPR in coronavirus (β-coronavirus and SARS-CoV-2) infection. SARS-CoV-2-infected lung epithelial cells show cell-autonomous UPR induction (yellow) in primary infected cells followed by transmission of cell-non-autonomous UPR (blue) to bystander cells via unknown biomolecules enhancing the pro-viral kinase NUAK2 that increases receptor abundance promoting the binding and uptake of SARS-CoV-2 (66). ß-coronaviruses promote the secretion of BiP from infected cells (67). (C)Niche and distal bystander non-infected cells with enhanced NUAK2 expression separated from SARS-CoV-2-infected cells using single-cell RNA-fluorescence in situ hybridization (FISH). Data are related to the study of Prasad et al. (66).