Global control of host antiviral responses by rotavirus NSP1
| dc.contributor.advisor | Beemon, Karen | |
| dc.contributor.committeeMember | Patton, John T | |
| dc.contributor.committeeMember | McDonald, Sarah | |
| dc.contributor.committeeMember | Cunningham, Kyle | |
| dc.creator | Davis, Kaitlin | |
| dc.date.accessioned | 2019-04-15T04:11:36Z | |
| dc.date.created | 2018-05 | |
| dc.date.issued | 2017-12-15 | |
| dc.date.submitted | May 2018 | |
| dc.date.updated | 2019-04-15T04:11:36Z | |
| dc.description.abstract | Rotaviruses are a leading cause of severe, life-threatening diarrhea worldwide, primarily in infants and young children. Interferon induction is a key protective host defense mechanism triggered during viral infection, and to combat this response, rotaviruses encode the primary interferon antagonist non-structural protein 1 (NSP1). Expression of NSP1 proteins from diverse rotavirus strains is associated with a decrease in interferon induction, and depending on host species and virus strain, may achieve this result by facilitating the degradation of various host signaling proteins. Most human and porcine strains, including the rotavirus strain OSU, encode an NSP1 capable of facilitating the degradation of β-TrCP, a key regulator of NF-κB-mediated interferon induction. β-TrCP acts as a substrate adaptor protein of cellular E3 ubiquitin ligases, and by directing degradation of IκB (inhibitor of kappa B), allows NF-κB to translocate to the nucleus to induce interferon responses. β-TrCP recognizes and binds a phosphorylated degron (phosphodegron) motif (DSGϕxS) within IκB, and other cellular proteins, to facilitate degradation. The C-terminus of OSU NSP1 harbors a mimic of this motif (DSGIS) that allows for binding and sequestration of β-TrCP. In our studies, we have found that like IκB, NSP1 is phosphorylated and requires phosphorylation for β-TrCP engagement. Unlike IκB, NSP1 is a substrate of casein kinase II (CKII). NSP1 is a substrate adaptor protein of cullin-RING ligases (CRLs), and while NSP1 appears to engage cullin 3 via an N-terminal RING domain, C-terminal degron phosphorylation is required for NSP1 incorporation into CRLs. Interestingly, NSP1 proteins that engage interferon response factor (IRF) proteins are able to engage these substrates without phosphorylation. These data suggest that NSP1 proteins may inhibit interferon induction through binding and sequestration alone, without the specific need for degradation of substrates. Furthermore, many viruses are known to encode proteins that directly engage and direct β-TrCP activity. β-TrCP regulates stability of proteins involved in a number of pathways beyond simply interferon induction, including mTOR. Our studies indicate that OSU infection results in accumulation of DEPTOR, a β-TrCP substrate and negative regulator of mTOR complexes. Analysis of mTOR signaling cascades suggests that control of β-TrCP may result in a pro-viral cellular environment with benefits to viruses beyond promoting rotavirus replication. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://jhir.library.jhu.edu/handle/1774.2/60952 | |
| dc.language.iso | en_US | |
| dc.publisher | Johns Hopkins University | |
| dc.publisher.country | USA | |
| dc.subject | rotavirus | |
| dc.subject | interferon, cullin | |
| dc.subject | ubiquitin | |
| dc.title | Global control of host antiviral responses by rotavirus NSP1 | |
| dc.type | Thesis | |
| dc.type.material | text | |
| local.embargo.lift | 2019-05-01 | |
| local.embargo.terms | 2019-05-01 | |
| thesis.degree.department | Biology | |
| thesis.degree.discipline | Biology | |
| thesis.degree.grantor | Johns Hopkins University | |
| thesis.degree.grantor | Krieger School of Arts and Sciences | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Ph.D. |