Herpes Simplex Type 1 UL43 Multiple Membrane-Spanning Protein Increases Energy Metabolism in Host Cells through Interacting with ARL2

Jianshan Deng; Zhiying Zhong; Chengxu Geng; Zhenning Dai; Weihan Zheng; Ziyue Li; Zi Yan; Jiaxin Yang; Wenfeng Deng; Wei Tan; Hanxiao Sun; Shiyu Li

doi:10.3390/cells11223594

Herpes Simplex Type 1 UL43 Multiple Membrane-Spanning Protein Increases Energy Metabolism in Host Cells through Interacting with ARL2

Cells. 2022 Nov 14;11(22):3594. doi: 10.3390/cells11223594.

Authors

Jianshan Deng¹, Zhiying Zhong¹, Chengxu Geng¹, Zhenning Dai^{2

3}, Weihan Zheng², Ziyue Li², Zi Yan², Jiaxin Yang⁴, Wenfeng Deng⁵, Wei Tan^{2

6}, Hanxiao Sun¹, Shiyu Li^{1

2

4}

Affiliations

¹ Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou 511436, China.
² Guangdong Medical Innovation Platform for Translation of 3D Printing Application, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou 510630, China.
³ Department of Stomatology, Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou 510095, China.
⁴ Department of Anatomy, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
⁵ Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510799, China.
⁶ Guangxi Key Laboratory of Birth Defects Research and Prevention, Nanning 530005, China.

Abstract

Non-essential proteins for viral replication affect host cell metabolism, while the function of the UL43 protein of herpes simplex virus 1 (HSV-1) is not clear. Herein, we performed a comprehensive microarray analysis of HUVEC cells infected with HSV-1 and its UL43-deficient mutant and found significant variation in genes associated with cellular energy metabolic pathways. The localization of UL43 protein in host cells and how it affects cellular energy metabolism pathways were further investigated. Internalization analysis showed that the UL43 protein could be endocytosis-mediated by YPLF motif (aa144-147) and localized to mitochondria. At the same time, more ATP was produced by coupling with mitochondrial small G protein ARF-like 2 (ARL2) GTPase, which triggered the phosphorylation of ANT1 (SLC25A4) to affect the opening degree of mitochondrial permeability transition pore (mPTP), and significantly promoted the aerobic oxidation and oxidative phosphorylation of glucose. Our study shows that UL43 mediates the improvement of host cell metabolism after HSV-1 infection. Additionally, UL43 protein could be a valuable ATP-stimulating factor for mammalian cells.

Keywords: ANT1; ATP generation; UL43 protein; herpes simplex virus type 1; small G protein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Animals
Energy Metabolism
Herpes Simplex*
Herpesvirus 1, Human* / metabolism
Mammals / metabolism
Membrane Proteins / metabolism
Oxidative Phosphorylation

Substances

Membrane Proteins
Adenosine Triphosphate

Grants and funding

This work was supported by National Natural Science Foundation of China (82073747), and Guangdong Basic and Applied Basic Research Foundation (2021A1515111074), and the fellowship of China Postdoctoral Science Foundation (2021M701620), Yingcai Project in Guangzhou Development District (2019 Year), Scientific research project of Traditional Chinese Medicine Bureau of Guangdong Province (20232007), President Foundation of The Third Affiliated Hospital of Southern Medical University (YQ2021001), Guangxi Key Laboratory of Birth Defects Research and Prevention (GXWCHZDKF-2022-21).