Nonstructural Protein σ1s Mediates Reovirus-Induced Cell Cycle Arrest and Apoptosis

Hammer, Katharina; Tollefson, William; Konopka-Anstadt, Jennifer L.; Kobayashi, Takeshi; Dermody, Terence S.

doi:10.1128/jvi.02080-13

Cited by 36 publications

(28 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, further work will be required to determine whether 1s functions to promote reovirus protein expression and replication in vivo. In addition to 2H11 and TX-111 cells, 1s is not required for replication in L929 and HeLa cells or in the intestines and CNS of infected mice (30,(32)(33)(34). A similar cell-type-specific requirement is observed for the virion host shutoff (vhs) protein from herpes simplex virus 2 (HSV-2).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Nonstructural Protein σ1s Is Required for Optimal Reovirus Protein Expression

Phillips

Stuart

Simon

2018

J Virol

Self Cite

View full text Add to dashboard Cite

Reovirus non-structural protein σ1s is required for the establishment of viremia and hematogenous viral dissemination. However, the function of the σ1s protein during the reovirus replication cycle is not known. In this study, we found that σ1s was required for efficient reovirus replication in SV40-immortalized endothelial cells (SVECs), mouse embryonic fibroblasts, human umbilical vein endothelial cells (HUVECs), and T84 human colonic epithelial cells. In each of these cell lines, wild type reovirus produced substantially higher viral titers than a σ1s-deficient mutant. The σ1s protein was not required for early events in the reovirus infection, as no difference in infectivity between the wild type and σ1s-null viruses was observed. However, wild type virus produced markedly higher viral protein levels than the σ1s-deficient strain. The disparity in viral replication did not result from differences in viral transcription or protein stability. We further found that the σ1s protein was dispensable for cell killing and induction of type-1 interferon responses. In the absence of σ1s, viral factory (VF) maturation was impaired, but sufficient to support low levels of reovirus replication. Together, our results indicate that σ1s is not absolutely essential for viral protein production, but rather potentiates reovirus protein expression to facilitate reovirus replication. Our findings suggest that σ1s enables hematogenous reovirus dissemination by promoting efficient viral protein synthesis, and thereby reovirus replication, in cells that are required for reovirus spread to the blood.Hematogenous dissemination is critical a step in the pathogenesis of many viruses. For reovirus, nonstructural protein σ1s is required for viral spread via the blood. However, the mechanism by σ1s promotes reovirus dissemination is unknown. Here, we identified σ1s as a viral mediator of reovirus protein expression. We found several cultured cell lines in which σ1s is required for efficient reovirus replication. In these cells, wild type virus produced substantially higher levels of viral protein than a σ1s-deficient mutant. The σ1s protein was not required for viral mRNA transcription or viral protein stability. Owing to reduced levels of viral protein synthesized in the absence of σ1s, maturation of viral factories was impaired and significantly fewer viral progeny were produced. Taken together, our findings indicate that σ1s is required for optimal reovirus protein production, and thereby viral replication, in cells required hematogenous reovirus dissemination.

show abstract

Section: Discussionmentioning

confidence: 99%

“…In infected cells, 1s is found throughout the cytoplasm and nucleus. However, the subcellular localization required for 1s function is unknown (30)(31)(32). In infected mice, 1s is required for hematogenous reovirus dissemination (33)(34)(35).…”

mentioning

confidence: 99%

Nonstructural Protein σ1s Is Required for Optimal Reovirus Protein Expression

Phillips

Stuart

Simon

2018

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…The μ1 protein impacts reovirus infectivity by enhancing reovirus attachment to cells (63). S1 is genetically linked to reovirus induction of apoptosis through the activities of both σ1 and σ1s, although it is unclear if the effects of σ1s on the induction of cell death are independent of its ability to regulate viral protein synthesis and induce cell cycle arrest (64, 65). We did not observe significant levels of cell cycle arrest in MDA-MB-231 cells infected with reassortant reoviruses (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

Stewart

Berry

Berger

et al. 2019

Preprint

View full text Add to dashboard Cite

20Breast cancer is the second-leading cause of cancer-related deaths in women in the 21 United States. Triple-negative breast cancer constitutes a subset of breast cancer that is 22 Importance 38Patients afflicted by triple-negative breast cancer have decreased survival and limited 39 therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is 40 unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, 41 we generated two novel reoviruses that more efficiently infect and kill triple-negative breast 42 cancer cells. We show that infection in the presence of DNA-damaging agents enhances 43 infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a 44 combination of a genetically engineered oncolytic reovirus and topoisomerase inhibitors may 45 provide a potent therapeutic option for patients afflicted with triple-negative breast cancer. 46 47Breast cancer is the leading cause of cancer and second leading cause of deaths by cancer 48 in women in the United States (1). Triple-negative breast cancer (TNBC) constitutes 49 approximately 15% of breast cancers, has a higher rate of relapse, and shorter overall survival 50 after metastasis than other subtypes of breast cancer (2). TNBC more frequently affects the 51 young, is more prevalent in African American women, and tumors are larger in size and 52 biologically more aggressive (3). TNBC is characterized by the lack of expression of estrogen 53 receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 54 (HER2/neu) and can be classified into seven subtypes based on their genetic signature (3). 55

show abstract

“…Primary murine cortical neurons were prepared from murine brain tissue at embryonic day 15 as described (Antar et al, 2009; Boehme et al, 2013a). L929 cells were maintained as described (Barton et al, 2001a).…”

Section: Methodsmentioning

confidence: 99%

The Nogo Receptor NgR1 Mediates Infection by Mammalian Reovirus

Konopka-Anstadt

Mainou

Sutherland

et al. 2014

Cell Host & Microbe

View full text Add to dashboard Cite

SUMMARY Neurotropic viruses, including mammalian reovirus, must disseminate from an initial site of replication to the central nervous system (CNS), often binding multiple receptors to facilitate systemic spread. Reovirus engages junctional adhesion molecule-A (JAM-A) to disseminate hematogenously. However, JAM-A is dispensable for reovirus replication in the CNS. We demonstrate that reovirus binds Nogo receptor NgR1, a leucine-rich-repeat protein expressed in the CNS, to infect neurons. Expression of NgR1 confers reovirus binding and infection of non-susceptible cells. Incubating reovirus virions with soluble NgR1 neutralizes infectivity. Blocking NgR1 on transfected cells or primary cortical neurons abrogates reovirus infection. Concordantly, reovirus infection is ablated in primary cortical neurons derived from NgR1-null mice. Reovirus virions bind to soluble JAM-A and NgR1, while infectious disassembly intermediates (ISVPs) bind only to JAM-A. These results suggest that reovirus uses different capsid components to bind distinct cell-surface molecules, engaging independent receptors to facilitate spread and tropism.

show abstract

Nonstructural Protein σ1s Mediates Reovirus-Induced Cell Cycle Arrest and Apoptosis

Cited by 36 publications

References 87 publications

Nonstructural Protein σ1s Is Required for Optimal Reovirus Protein Expression

Nonstructural Protein σ1s Is Required for Optimal Reovirus Protein Expression

Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

The Nogo Receptor NgR1 Mediates Infection by Mammalian Reovirus

Contact Info

Product

Resources

About