Endoplasmic Reticulum (ER) Stress Induced by a Neurovirulent Mouse Retrovirus Is Associated with Prolonged BiP Binding and Retention of a Viral Protein in the ER

Abstract

Some murine retroviruses cause a spongiform neurodegenerative disease exhibiting pathology resembling that observed in transmissible spongiform encephalopathies. The neurovirulence of these "spongiogenic retroviruses" is determined by the sequence of their respective envelope proteins, although the mechanisms of neurotoxicity are not understood. We have studied a highly neurovirulent virus called FrCas E that causes a rapidly progressive form of this disease. Recently, transcriptional markers of endoplasmic reticulum (ER) stress were detected during the early preclinical period in the brains of FrCas E -infected mice. In contrast, ER stress was not observed in mice infected with an avirulent virus, F43, which carries a different envelope gene, suggesting a role for ER stress in disease pathogenesis. Here we have examined in NIH 3T3 cells the cause of this cellular stress response. The envelope protein of F43 bound BiP, a major ER chaperone, transiently and was processed normally through the secretory pathway. In contrast, the envelope protein of FrCas E bound to BiP for a prolonged period, was retained in the ER, and was degraded by the proteasome. Furthermore, engagement of the FrCas E envelope protein by ER quality control pathways resulted in decreased steady-state levels of this protein, relative to that of F43, both in NIH 3T3 cells and in the brains of infected mice. Thus, the ER stress induced by FrCas E appears to be initiated by inefficient folding of its viral envelope protein, suggesting that the neurodegenerative disease caused by this virus represents a protein misfolding disorder.

Viruses, endoplasmic reticulum stress, and interferon responses

“…It has been reported that murine retroviruses cause a spongiform neurodegenerative disease, which is determined by properties of viral envelope proteins. 6 Infection of cells with the virulent strain FrCas E stimulates the expression of BiP and CHOP, whereas infection with an avirulent strain F43 has no effect. Importantly, the envelope protein from F43 binds to BiP transiently and is processed normally through the secretory pathway.…”

“…[3][4][5] Recent evidence has suggested the importance of ER stress response in virus infection. [5][6][7][8] As a processing plant for folding and post-translational modification of proteins, the ER is an essential organelle for viral replication and maturation. In the course of productive infection, a large amount of viral proteins are synthesized in infected cells, where unfolded or misfolded proteins activate the ER stress response.…”

Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration

“…Several studies of animal retroviruses have reported the induction of inflammation and ER stress-related genes in the brain (8)(9)(10)(11)(12). Similarly, glycoproteins encoded by other viruses, such as hepatitis C virus, are also capable of inducing pathogenic ER stress in other tissues (13)(14)(15).…”

Gene expression in primary cultured astrocytes affected by aluminum: alteration of chaperons involved in protein folding

“…Together with Ire1, PERK and ATF6 regulate components that act to suppress the initiation of protein synthesis, upregulate the capacity of the ER to fold newly synthesized proteins, and degrade misfolded/unfolded protein [4]. Under non-stressed conditions, Bip (Grp78), an ATPdependent ER chaperone, binds to the three ER resident transmembrane proteins (i.e., Ire1, PERK, and ATF6) which negatively regulate the UPR by keeping these proteins in an inactivated state [46]. When misfolded proteins accumulate in the ER, BiP/GRP78 binds instead to misfolded proteins [47][48][49] and allows activation of these UPR sensors, leading to decreased protein synthesis and the increased production of ER chaperones [46,50].…”