Pan-retroviral Nucleocapsid-Mediated Phase Separation Regulates Genomic RNA Positioning and Trafficking
| Autor: | Lois Chen, Shringar Rao, Robert James Gorelick, Meijuan Niu, Andrew J. Mouland, Anne Monette |
|---|---|
| Přispěvatelé: | Biochemistry |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
viruses General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Stress granule Retrovirus Organelle Humans Nucleocapsid lcsh:QH301-705.5 Ribonucleoprotein biology Chemistry Mutagenesis RNA Genomics biology.organism_classification Virus Release 3. Good health Cell biology Protein Transport 030104 developmental biology lcsh:Biology (General) Viral replication RNA Viral 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 31, Iss 3, Pp-(2020) Cell Reports, 31(3):Unsp 107520. Cell Press |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2020.03.084 |
| Popis: | Summary: The duality of liquid-liquid phase separation (LLPS) of cellular components into membraneless organelles defines the nucleation of both normal and disease processes including stress granule (SG) assembly. From mounting evidence of LLPS utility by viruses, we discover that HIV-1 nucleocapsid (NC) protein condenses into zinc-finger (ZnF)-dependent LLPSs that are dynamically influenced by cytosolic factors. ZnF-dependent and Zinc (Zn2+)-chelation-sensitive NC-LLPS are formed in live cells. NC-Zn2+ ejection reverses the HIV-1 blockade on SG assembly, inhibits NC-SG assembly, disrupts NC/Gag-genomic RNA (vRNA) ribonucleoprotein complexes, and causes nuclear sequestration of NC and the vRNA, inhibiting Gag expression and virus release. NC ZnF mutagenesis eliminates the HIV-1 blockade of SG assembly and repositions vRNA to SGs. We find that NC-mediated, Zn2+-coordinated phase separation is conserved among diverse retrovirus subfamilies, illustrating that this exquisitely evolved Zn2+-dependent feature of virus replication represents a critical target for pan-antiretroviral therapies. : Monette et al. discover a high degree of conservation of zinc-finger embedded, intrinsically disordered prion-like domains across retrovirus Gag proteins. These domains within the Gag Nucleocapsid regulate the formation of zinc-dependent liquid-liquid phase condensates and stress granules in HIV-1-expressing cells to induce repositioning of the viral genomic RNA. Keywords: HIV-1, retrovirus, Gag, viral genomic RNA trafficking, nucleocapsid, stress granule, liquid-liquid phase separation, membraneless organelle, intrinsically disordered domain, zinc |
| Databáze: | OpenAIRE |
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