Human herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: network analysis identifies interacting pathways

Author:

Webber Chelsea J12,Murphy Caroline N12,Rondón-Ortiz Alejandro N1234,van der Spek Sophie J F12,Kelly Elena X12,Lampl Noah M3,Chiesa Giulio56,Khalil Ahmad S567,Emili Andrew389,Wolozin Benjamin12101112ORCID

Affiliation:

1. Departments of Pharmacology , Physiology and Biophysics, , Boston, MA 02215 , USA

2. Boston University , Physiology and Biophysics, , Boston, MA 02215 , USA

3. Center for Network Systems Biology, Boston University , Boston, MA 02215 , USA

4. Department of Biology, Boston University , Boston, MA 02215 , USA

5. Biological Design Center, Boston University , Boston, MA 02215 , USA

6. Department of Biomedical Engineering, Boston University , Boston, MA 02215 , USA

7. Wyss Institute for Biologically Inspired Engineering, Harvard University , Boston, MA 02115 , USA

8. Department of Biochemistry, Boston University , Boston, MA 02115 , USA

9. Department of Biochemistry, Oregon Health Sciences University , Portland, OR 97239 , USA

10. Center for Systems Neuroscience, Boston University , Boston, MA 02115 , USA

11. Center for Neurophotonics, Boston University , Boston, MA 02115 , USA

12. Department of Neurology, Boston University , Boston, MA 02115 , USA

Abstract

Abstract Aggregation of TAR DNA-binding protein 43 kDa (TDP-43) is thought to drive the pathophysiology of amyotrophic lateral sclerosis and some frontotemporal dementias. TDP-43 is normally a nuclear protein that in neurons translocates to the cytoplasm and can form insoluble aggregates upon activation of the integrated stress response (ISR). Viruses evolved to control the ISR. In the case of Herpesvirus 8, the protein ORF57 acts to bind protein kinase R, inhibit phosphorylation of eIF2α and reduce activation of the ISR. We hypothesized that ORF57 might also possess the ability to inhibit aggregation of TDP-43. ORF57 was expressed in the neuronal SH-SY5Y line and its effects on TDP-43 aggregation characterized. We report that ORF57 inhibits TDP-43 aggregation by 55% and elicits a 2.45-fold increase in the rate of dispersion of existing TDP-43 granules. These changes were associated with a 50% decrease in cell death. Proteomic studies were carried out to identify the protein interaction network of ORF57. We observed that ORF57 directly binds to TDP-43 as well as interacts with many components of the ISR, including elements of the proteostasis machinery known to reduce TDP-43 aggregation. We propose that viral proteins designed to inhibit a chronic ISR can be engineered to remove aggregated proteins and dampen a chronic ISR.

Funder

BrightFocus Foundation

National Institutes of Health

Rainwater Charitable Foundation

Department of Defense Vannevar Bush Faculty Fellowship

Schmidt Science Polymath Award

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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