BIKE regulates dengue virus infection via CLINT1 phosphorylation and is a host target for broad-spectrum antivirals
Abstract/Contents
- Abstract
- The signaling pathways and functions that the four Numb-associated kinases (NAK) regulate are largely unknown. We reported that AAK1 and GAK control intracellular trafficking of RNA viruses. Nevertheless, the role of BIKE and STK16 in viral infection remained unknown. We reveal a requirement for BIKE in dengue virus (DENV) entry and assembly/egress. To identify BIKE substrates, we conducted a barcode fusion genetics-Yeast 2-Hybrid screen and retrieved publicly available data generated via affinity-purification mass spectrometry. Nineteen of 47 putative interactors were validated via mammalian cell-based protein-protein interaction assays. CLINT1, a cargo-specific adaptor implicated in bidirectional Golgi-to-endosome trafficking, emerged as a predominant hit in both screens. BIKE catalyzes phosphorylation of a threonine 294 (T294) CLINT1 residue both in vitro and in cells. CLINT1 phosphorylation mediates its binding to the DENV nonstructural 3 protein and subsequently DENV assembly and egress. CLINT1 cotraffics with DENV particles via live-cell imaging and is involved in mediating BIKE's role in DENV infection. Our data indicate that additional interactors implicated in the host immune and stress responses and the ubiquitin proteasome system are candidate phosphorylation substrates of BIKE. Lastly, pharmacological compounds with potent anti-BIKE activity suppress DENV infection both in vitro and ex vivo, exhibit activity against the unrelated Ebola virus, and their mechanism of antiviral action is in part mediated by BIKE. These findings reveal cellular substrates and pathways regulated by the understudied BIKE, mechanism for CLINT1 regulation, and control of DENV infection via BIKE signaling, with potential implications for cell biology, virology, and host-targeted antiviral design
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Schor, Stanford Jeremy |
|---|---|
| Degree supervisor | Einav, Shirit |
| Thesis advisor | Einav, Shirit |
| Thesis advisor | Felsher, Dean (Dean Walton) |
| Thesis advisor | Glenn, Jeffrey S, 1962- |
| Thesis advisor | Jackson, Peter K. (Peter Kent) |
| Degree committee member | Felsher, Dean (Dean Walton) |
| Degree committee member | Glenn, Jeffrey S, 1962- |
| Degree committee member | Jackson, Peter K. (Peter Kent) |
| Associated with | Stanford University, Cancer Biology Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Stanford Jeremy Schor |
|---|---|
| Note | Submitted to the Cancer Biology Program |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Stanford Jeremy Schor
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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