The African swine fever virus I73R protein is a multifunctional Zα domain that mediates both Z-binding-dependent and -independent biological functions through induction of phase separation
4 affiliations
- 1Virology-Vaccinology, Department of Infectious and Parasitic Diseases, Fundamental and Applied Research for Animals & Health (FARAH), Faculty of Veterinary Medicine, University of Liège , Liège B-4000 ,
- 2State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University , Beijing 100193 ,
- 3Department of Chemistry, Sungkyunkwan University , Suwon 16419 ,
- 4Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University , Guangzhou, Guangdong 510642 ,
Abstract
African swine fever virus (ASFV) I73R encodes a protein consisting only of a Zalpha (Zα) domain. Here, we studied its biochemical properties. Complementary approaches demonstrated that I73R is a multifunctional Zα domain that combines Z-binding, B-to-Z conversion, and liquid-liquid phase separation (LLPS) induction activities. I73R proved to be a better converter than human ADAR1 Zα, and it retained conversion activity with Y48I mutation of its Z-binding site. Next, we investigated I73R biological functions, leading to the following findings: (i) Ectopic expression of I73R or mutated I73R with deficient Z-binding both inhibited arsenite-induced stress granules to a similar extent, and none of these proteins localized within these organelles. (ii) I73R formed cytosolic condensates with dsRNA, Z-DNA, and Z-RNA in ASFV-infected cells. (iii) Rescuing of ASFV I73R deletion by sequences encoding natural, mutated, and chimeric forms of Zα domains demonstrated that I73R mediated both Z-binding-dependent and -independent biological functions through induction of LLPS. This conclusion was further supported by the effect of the LLPS inhibitor 1,6-hexanediol on the replication of ASFV I73R recombinant strains. This study further demonstrates the functional diversity that exists among Zα domains. It unravels new outlooks targeting Zα domain-mediated LLPS for the development of pharmaceutical molecules able to regulate viral and cellular Zα domain-containing proteins.
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BibTeX
@article{pirotte2026african,
title = {{The African swine fever virus I73R protein is a multifunctional Zα domain that mediates both Z-binding-dependent and -independent biological functions through induction of phase separation}},
author = {Sébastien Pirotte and Yingnan Liu and Laurie Conti and Lisa Conti and Hyuk Won and Seon Jeong Im and Cédrik Ferhad and Yunlong Hu and Owen Donohoe and Mamadou Amadou Diallo and Lang Gong and Rongrong Wang and Yang-Gyun Kim and Hongjun Chen and Alain Vanderplasschen},
journal = {Nucleic Acids Research},
year = {2026},
month = oct,
doi = {10.1093/nar/gkag1008},
url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1008/9010736},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - The African swine fever virus I73R protein is a multifunctional Zα domain that mediates both Z-binding-dependent and -independent biological functions through induction of phase separation
AU - Sébastien Pirotte
AU - Yingnan Liu
AU - Laurie Conti
AU - Lisa Conti
AU - Hyuk Won
AU - Seon Jeong Im
AU - Cédrik Ferhad
AU - Yunlong Hu
AU - Owen Donohoe
AU - Mamadou Amadou Diallo
AU - Lang Gong
AU - Rongrong Wang
AU - Yang-Gyun Kim
AU - Hongjun Chen
AU - Alain Vanderplasschen
PY - 2026
DA - 2026/10/01
JO - Nucleic Acids Research
DO - 10.1093/nar/gkag1008
UR - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1008/9010736
AB - African swine fever virus (ASFV) I73R encodes a protein consisting only of a Zalpha (Zα) domain. Here, we studied its biochemical properties. Complementary approaches demonstrated that I73R is a multifunctional Zα domain that combines Z-binding, B-to-Z conversion, and liquid-liquid phase separation (LLPS) induction activities. I73R proved to be a better converter than human ADAR1 Zα, and it retained conversion activity with Y48I mutation of its Z-binding site. Next, we investigated I73R biological functions, leading to the following findings: (i) Ectopic expression of I73R or mutated I73R with deficient Z-binding both inhibited arsenite-induced stress granules to a similar extent, and none of these proteins localized within these organelles. (ii) I73R formed cytosolic condensates with dsRNA, Z-DNA, and Z-RNA in ASFV-infected cells. (iii) Rescuing of ASFV I73R deletion by sequences encoding natural, mutated, and chimeric forms of Zα domains demonstrated that I73R mediated both Z-binding-dependent and -independent biological functions through induction of LLPS. This conclusion was further supported by the effect of the LLPS inhibitor 1,6-hexanediol on the replication of ASFV I73R recombinant strains. This study further demonstrates the functional diversity that exists among Zα domains. It unravels new outlooks targeting Zα domain-mediated LLPS for the development of pharmaceutical molecules able to regulate viral and cellular Zα domain-containing proteins.
SN - 0305-1048
SN - 1362-4962
ER -