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Article

Overexpression of UBA5 in Cells Mimics the Phenotype of Cells Lacking UBA5

by
Sujata Kumari
1,2,
Sayanika Banerjee
1,
Manoj Kumar
1,
Arata Hayashi
1,
Balakrishnan Solaimuthu
1,
Einav Cohen-Kfir
1,
Yoav D. Shaul
1,
Alexander Rouvinski
2 and
Reuven Wiener
1,*
1
Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
2
Department of Microbiology and Molecular Genetics, The Institute for Medical Research Israel-Canada, The Kuvin Center for the Study of Infectious and Tropical Diseases, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(13), 7445; https://doi.org/10.3390/ijms23137445
Submission received: 29 May 2022 / Revised: 28 June 2022 / Accepted: 30 June 2022 / Published: 4 July 2022
(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)
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Abstract

Ufmylation is a posttranslational modification in which the modifier UFM1 is attached to target proteins. This conjugation requires the concerted work of three enzymes named UBA5, UFC1, and UFL1. Initially, UBA5 activates UFM1 in a process that ends with UFM1 attached to UBA5’s active site Cys. Then, in a trans-thiolation reaction, UFM1 is transferred from UBA5 to UFC1, forming a thioester bond with the latter. Finally, with the help of UFL1, UFM1 is transferred to the final destination—a lysine residue on a target protein. Therefore, not surprisingly, deletion of one of these enzymes abrogates the conjugation process. However, how overexpression of these enzymes affects this process is not yet clear. Here we found, unexpectedly, that overexpression of UBA5, but not UFC1, damages the ability of cells to migrate, in a similar way to cells lacking UBA5 or UFC1. At the mechanistic level, we found that overexpression of UBA5 reverses the trans-thiolation reaction, thereby leading to a back transfer of UFM1 from UFC1 to UBA5. This, as seen in cells lacking UBA5, reduces the level of charged UFC1 and therefore harms the conjugation process. In contrast, co-expression of UBA5 with UFM1 abolishes this effect, suggesting that the reverse transfer of UFM1 from UFC1 to UBA5 depends on the level of free UFM1. Overall, our results propose that the cellular expression level of the UFM1 conjugation enzymes has to be tightly regulated to ensure the proper directionality of UFM1 transfer.
Keywords: ufmylation; UBA5; UFC1; E1-activating enzymes; E2-conjugating enzymes; ubiquitin-like protein; UFM1 ufmylation; UBA5; UFC1; E1-activating enzymes; E2-conjugating enzymes; ubiquitin-like protein; UFM1
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MDPI and ACS Style

Kumari, S.; Banerjee, S.; Kumar, M.; Hayashi, A.; Solaimuthu, B.; Cohen-Kfir, E.; Shaul, Y.D.; Rouvinski, A.; Wiener, R. Overexpression of UBA5 in Cells Mimics the Phenotype of Cells Lacking UBA5. Int. J. Mol. Sci. 2022, 23, 7445. https://doi.org/10.3390/ijms23137445

AMA Style

Kumari S, Banerjee S, Kumar M, Hayashi A, Solaimuthu B, Cohen-Kfir E, Shaul YD, Rouvinski A, Wiener R. Overexpression of UBA5 in Cells Mimics the Phenotype of Cells Lacking UBA5. International Journal of Molecular Sciences. 2022; 23(13):7445. https://doi.org/10.3390/ijms23137445

Chicago/Turabian Style

Kumari, Sujata, Sayanika Banerjee, Manoj Kumar, Arata Hayashi, Balakrishnan Solaimuthu, Einav Cohen-Kfir, Yoav D. Shaul, Alexander Rouvinski, and Reuven Wiener. 2022. "Overexpression of UBA5 in Cells Mimics the Phenotype of Cells Lacking UBA5" International Journal of Molecular Sciences 23, no. 13: 7445. https://doi.org/10.3390/ijms23137445

APA Style

Kumari, S., Banerjee, S., Kumar, M., Hayashi, A., Solaimuthu, B., Cohen-Kfir, E., Shaul, Y. D., Rouvinski, A., & Wiener, R. (2022). Overexpression of UBA5 in Cells Mimics the Phenotype of Cells Lacking UBA5. International Journal of Molecular Sciences, 23(13), 7445. https://doi.org/10.3390/ijms23137445

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