Immune regulation of the unfolded protein response at the mucosal barrier in viral infection

Wang, Ran; Moniruzzaman, Md.; Shuffle, Eric; Lourie, Rohan; Hasnain, Sumaira Z.

doi:10.1002/cti2.1014

Cited by 13 publications

(12 citation statements)

References 96 publications

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“…In many viral infections, viruses commandeer vital cellular components, leading to cellular stress. Cellular stress is often represented as unfolded protein response (UPR) in cells (Geller et al, 2012; Wang et al, 2018). Previous studies have reported that ORF3 and ORF2 of the virus induce UPR and ER stress (Surjit et al, 2007; John et al, 2011; Xu et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Protein Interactions Network of Hepatitis E Virus RNA and Polymerase With Host Proteins

Kanade¹,

Pingale²,

Karpe³

2019

Front. Microbiol.

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Host-pathogen interactions are crucial for the successful propagation of pathogens inside the host cell. Knowledge of interactions between host proteins and viral proteins or viral RNA may provide clues for developing novel antiviral strategies. Hepatitis E virus (HEV), a water-borne pathogen that causes acute hepatitis in humans, is responsible for epidemics in developing countries. HEV pathology and molecular biology have been poorly explored due to the lack of efficient culture systems. A contemporary approach, to better understand the viral infection cycle at the molecular level, is the use of system biology tools depicting virus-host interactions. To determine the host proteins which participate in the regulation of HEV replication, we indentified liver cell proteins interacting with HEV RNA at its putative promoter region and those interacting with HEV polymerase (RdRp) protein. We employed affinity chromatography followed by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) to identify the interacting host proteins. Protein-protein interaction networks (PPI) were plotted and analyzed using web-based tools. Topological analysis of the network revealed that the constructed network is potentially significant and relevant for viral replication. Gene ontology and pathway enrichment analysis revealed that HEV RNA promoter- and polymerase-interacting host proteins belong to different cellular pathways such as RNA splicing, RNA metabolism, protein processing in endoplasmic reticulum, unfolded protein response, innate immune pathways, secretory vesicle pathway, and glucose metabolism. We showed that hnRNPK and hnRNPA2B1 interact with both HEV putative promoters and HEV RdRp, which suggest that they may have crucial roles in HEV replication. We demonstrated in vitro binding of hnRNPK and hnRNPA2B1 proteins with the HEV targets in the study, assuring the authenticity of the interactions obtained through mass spectrometry. Thus, our study highlights the ability of viruses, such as HEV, to maneuver host systems to create favorable cellular environments for virus propagation. Studying the host-virus interactions can facilitate the identification of antiviral therapeutic strategies and novel targets.

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Section: Resultsmentioning

confidence: 99%

Protein Interactions Network of Hepatitis E Virus RNA and Polymerase With Host Proteins

Kanade¹,

Pingale²,

Karpe³

2019

Front. Microbiol.

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“…Interestingly, Ca 2+ flux also facilitates the induction of ER stress during CVB infection ( 40 , 62 – 66 ). While ironclad proof of direct causality has remained elusive, CVB infection is highly associated with T1D onset in humans ( 67 – 75 ). Furthermore, a number of studies have defined footprints of CVB infection in the islets, demonstrated through the presence of RNA and VP1 antibody staining ( 70 , 74 , 76 – 80 ).…”

Section: Er Stress In β Cells Is Influenced By Immunologic and Enviromentioning

confidence: 99%

The Role of β Cell Stress and Neo-Epitopes in the Immunopathology of Type 1 Diabetes

Piganelli

Mamula

James³

2021

Front. Endocrinol.

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Due to their secretory function, β cells are predisposed to higher levels of endoplasmic reticulum (ER) stress and greater sensitivity to inflammation than other cell types. These stresses elicit changes in β cells that alter their function and immunogenicity, including defective ribosomal initiation, post-translational modifications (PTMs) of endogenous β cell proteins, and alternative splicing. Multiple published reports confirm the presence of not only CD8+ T cells, but also autoreactive CD4+ T cells within pancreatic islets. Although the specificities of T cells that infiltrate human islets are incompletely characterized, they have been confirmed to include neo-epitopes that are formed through stress-related enzymatic modifications of β cell proteins. This article summarizes emerging knowledge about stress-induced changes in β cells and data supporting a role for neo-antigen formation and cross-talk between immune cells and β cells that provokes autoimmune attack - leading to a breakdown in tissue-specific tolerance in subjects who develop type 1 diabetes.

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“…Multiple reports in the past have shed light on the cell's UPR pathway to ER stress and have shown that these three legs of UPR when functioning properly can lead to either the alleviation of stress and, hence, survival of the cell or stimulation of apoptosis pathways that lead to cell death (3,(9)(10)(11). These checks and balances not only ensure healthy maintenance of the cell but also protect a colony of cells from external infections (1,9,12,13).…”

Section: Introductionmentioning

confidence: 99%

Standalone or combinatorial phenylbutyrate therapy shows excellent antiviral activity and mimics CREB3 silencing

et al. 2020

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Herpesviruses are ubiquitous human pathogens that tightly regulate many cellular pathways including the unfolded protein response to endoplasmic reticulum (ER) stress. Pharmacological modulation of this pathway results in the inhibition of viral replication. In this study, we tested 4-phenylbutyrate (PBA), a chemical chaperone–based potent alleviator of ER stress, for its effects on herpes simplex virus (HSV) type 1 infection. Through in vitro studies, we observed that application of PBA to HSV-infected cells results in the down-regulation of a proviral, ER-localized host protein CREB3 and a resultant inhibition of viral protein synthesis. PBA treatment caused viral inhibition in cultured human corneas and human skin grafts as well as murine models of ocular and genital HSV infection. Thus, we propose that this drug can provide an alternative to current antivirals to treat both ocular HSV-1 and genital HSV-2 infections and may be a strong candidate for human trials.

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Immune regulation of the unfolded protein response at the mucosal barrier in viral infection

Cited by 13 publications

References 96 publications

Protein Interactions Network of Hepatitis E Virus RNA and Polymerase With Host Proteins

Protein Interactions Network of Hepatitis E Virus RNA and Polymerase With Host Proteins

The Role of β Cell Stress and Neo-Epitopes in the Immunopathology of Type 1 Diabetes

Standalone or combinatorial phenylbutyrate therapy shows excellent antiviral activity and mimics CREB3 silencing

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