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Literature detail

Coronavirus protein interaction mapping in bat and human cells reveals network rewiring governing immune evasion and zoonotic potential.

Jyoti Batra1,2,3,4 Magdalena Rutkowska5,6 Yuan Zhou1,2,3,4 Chengjin Ye7 Rithika Adavikolanu1,2,3,4 Janet M Young8 Durga Anand1,2,3,4 Sooraj Verma1,2,3,4 Haripriya Parthasarathy1,2,3,4 Martin Gordon1,2,3,4 Shivali Malpotra1,2,3,4 Anastasija Cupic5,6 Thomas Kehrer9 Melanie Dos Santos10 Ronald Benjamin1,2,3,4 Jack M Moen1,2,3,4 Declan M Winters11,12 Vincent Caval13 Ajda Rojc1,2,3,4 Ignacio Mena5,14,15 Sadaf Aslam9 Carles Martinez-Romero5,14,16 Isabela Conde Viñas5,17 Zain Khalil18 Keith Farrugia18 Fernando Villalón-Letelier9 Atoshi Banerjee1,2,3,4 Dafna Tussia-Cohen19 Amy Diallo2,20 Sourobh Maji2,20 Monita Muralidharan1,2,3,4 Helene Foussard1,2,3,4 Irene P Chen1,3,21 Rotem Fuchs19 C J San Felipe2,20 Lorena Zuliani-Alvarez1,2,3,4 Promisree Choudhury1,2,3,4 Kirsten Obernier1,2,3,4 Ségolène Gracias13 Rahul K Suryawanshi1,22 Boris Bonaventure9 Carlos Ibáñez23 Jeffrey R Johnson5,17 Javier Juste24,25 Lars Pache26 Robert M Stroud2,20 Kliment A Verba2,20 James S Fraser2,20 Harm van Bakel5,27,28,29 Taha Y Taha1,4 Melanie Ott1,2,3,30,31 Tzachi Hagai19 Nolwenn Jouvenet13 Caroline Demeret10 Benjamin J Polacco1,2,3,4 Danielle L Swaney1,2,3,4 Ignacia Echeverria2,3,4 Mehdi Bouhaddou11,12 Manon Eckhardt1,2,3,4 Harmit S Malik32,33 Luis Martinez-Sobrido7 Lisa Miorin5,34 Adolfo García-Sastre5,14,35,36,37,38 Nevan J Krogan1,2,3,39
Affiliations 39 institutions
  1. J. David Gladstone Institutes, San Francisco, CA 94158, USA
  2. Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA
  3. QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA
  4. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  5. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  6. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  7. Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
  8. Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  9. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  10. Interactomics, RNA and Immunity Laboratory, Institut Pasteur, Université Paris Cité, Paris 75015, France.
  11. Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California, Los Angeles, Los Angeles, CA 90024, USA
  12. Institute for Quantitative and Computational Biosciences (QCBio), University of California, Los Angeles, Los Angeles, CA 90024, USA.
  13. Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Virus sensing and signaling Unit, Paris 75015, France.
  14. Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  15. The Scripps Research Institute, Immunology and Microbiology Department, La Jolla, CA 92037, USA.
  16. Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  17. Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  18. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  19. Shmunis School of Biomedicine and Cancer Research, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.
  20. QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA.
  21. Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
  22. Laboratory of Neurological Infections and Immunity, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, Hamilton, MT 59840, USA.
  23. Estación Biológica de Doñana (CSIC), Avda. Américo Vespucio 26, 41092 Seville, Spain.
  24. Estación Biológica de Doñana (CSIC), Avda. Américo Vespucio 26, 41092 Seville, Spain
  25. CIBER Epidemiology and Public Health, CIBERESP, 28029 Madrid, Spain.
  26. NCI Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  27. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  28. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  29. Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  30. Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA
  31. Biohub, San Francisco, CA 94158, USA.
  32. Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
  33. Howard Hughes Medical Institute, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  34. Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: [email protected].
  35. Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  36. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  37. The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  38. Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: [email protected].
  39. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].
PMID 42134328 2026 Cell Host Microbe eng aheadofprint
PubMed DOI Browse context

Article

Publication summary

Coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause severe disease in humans, whereas reservoir hosts such as horseshoe bats remain asymptomatic. To investigate how host-specific protein-protein interactions (PPIs) influence infection, we generated comparative PPI maps for SARS-CoV-2 and its bat progenitor RaTG13, using affinity purification mass spectrometry (AP-MS) in human and greater horseshoe bat cells. We identify both conserved and virus- and host-specific interactions that regulate infection dynamics. Notably, SARS-CoV-2 requires a nonsynonymous mutation in the nucleocapsid to replicate in bat cells expressing human ACE2 and TMPRSS2. Strikingly, a single amino acid difference in Orf9b between viruses acts as a molecular switch that reprograms mitochondrial targeting: in human cells, enhanced translocase of outer mitochondrial membrane 70 (Tom70) binding promotes immune evasion, whereas in bat cells, strengthened interaction with the bat-enriched restriction factor mitochondrial amidoxime reducing component 2 (MTARC2) limits infection. These findings establish a general principle by which minimal sequence variation can reshape virus-host interactions and contribute to immune antagonism, host adaptation, and species barriers.

bats coronaviruses host-pathogen interaction MTARC2 proteomics RaTG13 SARS-CoV-2 Tom70 viral reservoirs virus-host tropism

Structured evidence records

Evidence records

2 total
Molecular Adaptation 2 records
Molecular Adaptation Extraction confidence 0.95
Key finding

A single amino acid difference in Orf9b between SARS-CoV-2 and RaTG13 acts as a molecular switch, redirecting binding between Tom70 and MTARC2, thereby modulating immune evasion and viral adaptation to human versus bat hosts.

Location
Not specified
Supporting text

A single amino acid difference in Orf9b between viruses acts as a molecular switch that reprograms mitochondrial targeting: in human cells, enhanced Tom70 binding promotes immune evasion, whereas in bat cells, strengthened interaction with MTARC2 limits infection.

Method
affinity purification mass spectrometry | protein-protein interaction mapping
Sample type
bat cells | human cells
Study design
in vitro experiment
Transmission direction
molecular mechanism only
Event type
host-specific protein interactions governing immune evasion
Genes or proteins
Orf9b | Tom70 | MTARC2
Host factors
Tom70 | MTARC2
Mutations
single amino acid difference in Orf9b
Mechanism types
immune evasion | mitochondrial targeting specificity
Molecular Adaptation Extraction confidence 0.93
Key finding

A nonsynonymous mutation in the SARS-CoV-2 nucleocapsid protein enables replication in bat cells expressing human ACE2 and TMPRSS2, highlighting a molecular adaptation influencing cross-species infectivity.

Location
Not specified
Supporting text

Notably, SARS-CoV-2 requires a nonsynonymous mutation in the nucleocapsid to replicate in bat cells expressing human ACE2 and TMPRSS2.

Method
affinity purification mass spectrometry | protein-protein interaction mapping
Sample type
bat cells | human cells
Study design
in vitro experiment
Transmission direction
molecular mechanism only
Event type
mutation affecting bat cell replication
Genes or proteins
nucleocapsid
Receptors
ACE2 | TMPRSS2
Mutations
nonsynonymous mutation in nucleocapsid
Mechanism types
replication in heterologous host cells