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Sindbis virus nonstructural protein nsP2 is cytotoxic and inhibits cellular transcription

Natalia Garmashova1, Rodion Gorchakov, Elena Frolova

  • 1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1019, USA.

Journal of Virology
|May 30, 2006
PubMed

Insights

Sindbis virus nsP2 protein is crucial for causing cell damage and death. Its ability to halt cellular transcription, independent of protease activity, drives this cytotoxic effect.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • Alphavirus replication induces cytopathic effects (CPE) and cell death in vertebrate cells.
  • Sindbis virus (SIN) replication significantly alters cellular macromolecular synthesis, notably downregulating mRNA and rRNA transcription.
  • The SIN nonstructural protein nsP2 has been implicated as a key regulator of virus-host interactions and CPE.

Purpose of the Study:

  • To investigate the role of SIN nsP2 in CPE development and its underlying mechanisms.
  • To determine if nsP2's cytotoxic function is linked to its transcriptional shutoff ability.
  • To identify the specific domains and forms of nsP2 responsible for its cytotoxic effects.

Main Methods:

  • Expression of SIN nsP2 alone and from different cassettes.
  • Analysis of SIN nsP2 mutants with alterations in the carboxy-terminal region.
  • Assessment of transcriptional activity and CPE in infected/transfected cells.
  • Evaluation of P123 processing and its impact on nsP2 activity.

Main Results:

  • SIN nsP2 is essential for CPE development, both during viral RNA replication and when expressed independently.
  • The cytotoxic effect of nsP2 is significantly mediated by its capacity to induce transcriptional shutoff.
  • The integrity of the carboxy-terminal peptide of nsP2, outside its helicase/protease domains, is critical for its functions.
  • Free, unprocessed nsP2 is required for CPE; alterations in P123 processing abolish this activity.

Conclusions:

  • SIN nsP2 is a primary driver of alphavirus-induced CPE, primarily through transcriptional inhibition.
  • The carboxy-terminal region of nsP2, rather than its protease activity, dictates its cytotoxic and transcriptional shutoff functions.
  • nsP2's cytotoxic activity is dependent on its free form, highlighting the importance of proper viral polyprotein processing for cell fate during infection.

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