2. Academic Validation
  3. Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production

Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production

  • EMBO J. 2024 Oct;43(20):4625-4655. doi: 10.1038/s44318-024-00193-3.
Zhenlan Yao 1,  Sangeetha Ramachandran 1,  Serina Huang 2,  Erin Kim 3,  Yasaman Jami-Alahmadi 4,  Prashant Kaushal 1 5 6,  Mehdi Bouhaddou 1 5 6,  James A Wohlschlegel 4,  Melody Mh Li 7 8
Affiliations

Affiliations

  • 1 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • 2 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • 3 Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • 4 Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • 5 Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA.
  • 6 Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA.
  • 7 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. Manhingli@mednet.ucla.edu.
  • 8 Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. Manhingli@mednet.ucla.edu.
PMID: 39261662 DOI: 10.1038/s44318-024-00193-3
Abstract

Despite their role as innate sentinels, macrophages can serve as cellular reservoirs of chikungunya virus (CHIKV), a highly-pathogenic arthropod-borne alphavirus that has caused large outbreaks among human populations. Here, with the use of viral chimeras and evolutionary selection analysis, we define CHIKV glycoproteins E1 and E2 as critical for virion production in THP-1 derived human macrophages. Through proteomic analysis and functional validation, we further identify signal peptidase complex subunit 3 (SPCS3) and eukaryotic translation initiation factor 3 subunit K (eIF3k) as E1-binding host proteins with anti-CHIKV activities. We find that E1 residue V220, which has undergone positive selection, is indispensable for CHIKV production in macrophages, as its mutation attenuates E1 interaction with the host restriction factors SPCS3 and eIF3k. Finally, we show that the Antiviral activity of eIF3k is translation-independent, and that CHIKV Infection promotes eIF3k translocation from the nucleus to the cytoplasm, where it associates with SPCS3. These functions of CHIKV glycoproteins late in the viral life cycle provide a new example of an intracellular evolutionary arms race with host restriction factors, as well as potential targets for therapeutic intervention.

Keywords

Alphavirus E1 Glycoprotein; Chikungunya Virus; Evolutionary Selection; Macrophage; eIF3k.

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