Glutamine metabolism is essential for coronavirus replication in host cells and in mice

Greene, Kai Su, Choi, Annette, Yang, Nianhui, Chen, Matthew, Li, Ruizhi, Qiu, Yijian, Ezzatpour, Shahrzad, Rojas, Katherine S, Shen, Jonathan, Wilson, Kristin F, Katt, William P, Aguilar, Hector C, Lukey, Michael J, Whittaker, Gary R, Cerione, Richard A (December 2024) Glutamine metabolism is essential for coronavirus replication in host cells and in mice. Journal of Biological Chemistry, 301 (1). p. 108063. ISSN 0021-9258

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Abstract

Understanding the fundamental biochemical and metabolic requirements for the replication of coronaviruses within infected cells is of notable interest for the development of broad-based therapeutic strategies, given the likelihood of the emergence of new pandemic-potential virus species, as well as future variants of SARS-CoV-2. Here we demonstrate members of the glutaminase family of enzymes (GLS and GLS2), which catalyze the hydrolysis of glutamine to glutamate (i.e., the first step in glutamine metabolism), play key roles in coronavirus replication in host cells. Using a range of human seasonal and zoonotic coronaviruses, we show three examples where GLS expression increases during coronavirus infection of host cells, and another where GLS2 is upregulated. The viruses hijack the metabolic machinery responsible for glutamine metabolism to generate the building blocks for biosynthetic processes and satisfy the bioenergetic requirements demanded by the "glutamine addiction" of virus-infected cells. We demonstrate that genetic silencing of glutaminase enzymes reduces coronavirus infection and that newer members of two classes of allosteric inhibitors targeting these enzymes, designated as SU1, a pan-GLS/GLS2 inhibitor, and UP4, a specific GLS inhibitor, block viral replication in epithelial cells. Moreover, treatment of SARS-CoV-2 infected K18-human ACE2 transgenic mice with SU1 resulted in their complete survival compared to untreated control animals, which succumbed within 10 days post-infection. Overall, these findings highlight the importance of glutamine metabolism for coronavirus replication in human cells and mice and show that glutaminase inhibitors can block coronavirus infection and thereby may represent a novel class of broad-based anti-viral drug candidates.

Item Type:	Paper
Subjects:	diseases & disorders diseases & disorders > viral diseases organism description > animal diseases & disorders > viral diseases > coronavirus diseases & disorders > viral diseases > coronavirus > covid 19 organism description > animal > mammal organism description > animal > mammal > rodent > mouse organism description > animal > mammal > rodent
CSHL Authors:	Qiu, Yijian Lukey, Michael
Communities:	CSHL labs > Lukey lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	9 December 2024
Date Deposited:	13 Jan 2025 18:13
Last Modified:	13 Jan 2025 18:13
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41770

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