LOX-1 acts as an N6-methyladenosine-regulated receptor for Helicobacter pylori by binding to the bacterial catalase

Judeng Zeng; Chuan Xie; Ziheng Huang; Chi H Cho; Hung Chan; Qing Li; Hassan Ashktorab; Duane T Smoot; Sunny H Wong; Jun Yu; Wei Gong; Cong Liang; Hongzhi Xu; Huarong Chen; Xiaodong Liu; Justin C Y Wu; Margaret Ip; Tony Gin; Lin Zhang; Matthew T V Chan; Wei Hu; William K K Wu

doi:10.1038/s41467-024-44860-9

LOX-1 acts as an N⁶-methyladenosine-regulated receptor for Helicobacter pylori by binding to the bacterial catalase

Nat Commun. 2024 Jan 22;15(1):669. doi: 10.1038/s41467-024-44860-9.

Authors

Judeng Zeng^#^{1

2

3}, Chuan Xie^#^{1

2

4}, Ziheng Huang^{1

2

3}, Chi H Cho⁵, Hung Chan^{1

2

3}, Qing Li^{1

2

3}, Hassan Ashktorab^{6

7

8}, Duane T Smoot⁹, Sunny H Wong¹⁰, Jun Yu^{1

3

11}, Wei Gong^{12

13}, Cong Liang¹⁴, Hongzhi Xu¹⁵, Huarong Chen^{1

2

3}, Xiaodong Liu^{2

3}, Justin C Y Wu^{1

11}, Margaret Ip^{3

16}, Tony Gin², Lin Zhang^{17

18

19

20}, Matthew T V Chan^{21

22}, Wei Hu^{23

24}, William K K Wu^{25

26

27}

Affiliations

¹ State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
² Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
³ CUHK Shenzhen Research Institute, Shenzhen, China.
⁴ Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi Province, China.
⁵ Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.
⁶ Department of Medicine, Howard University, Washington, DC, USA.
⁷ Cancer Center, Howard University, Washington, DC, USA.
⁸ Howard University Hospital, Howard University, Washington, DC, USA.
⁹ Department of Internal Medicine, Meharry Medical College, Nashville, TN, USA.
¹⁰ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
¹¹ Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
¹² Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China.
¹³ The Third School of Clinical Medicine, Southern Medical University, Shenzhen, Guangdong, China.
¹⁴ State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, China.
¹⁵ Institute for Microbial Ecology, School of Medicine, Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, China.
¹⁶ Department of Microbiology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
¹⁷ State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China. [email protected].
¹⁸ Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China. [email protected].
¹⁹ CUHK Shenzhen Research Institute, Shenzhen, China. [email protected].
²⁰ Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China. [email protected].
²¹ Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China. [email protected].
²² CUHK Shenzhen Research Institute, Shenzhen, China. [email protected].
²³ Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China. [email protected].
²⁴ The Third School of Clinical Medicine, Southern Medical University, Shenzhen, Guangdong, China. [email protected].
²⁵ State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China. [email protected].
²⁶ Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China. [email protected].
²⁷ CUHK Shenzhen Research Institute, Shenzhen, China. [email protected].

^# Contributed equally.

Abstract

The role of N⁶-methyladenosine (m⁶A) modification of host mRNA during bacterial infection is unclear. Here, we show that Helicobacter pylori infection upregulates host m⁶A methylases and increases m⁶A levels in gastric epithelial cells. Reducing m⁶A methylase activity via hemizygotic deletion of methylase-encoding gene Mettl3 in mice, or via small interfering RNAs targeting m⁶A methylases, enhances H. pylori colonization. We identify LOX-1 mRNA as a key m⁶A-regulated target during H. pylori infection. m⁶A modification destabilizes LOX-1 mRNA and reduces LOX-1 protein levels. LOX-1 acts as a membrane receptor for H. pylori catalase and contributes to bacterial adhesion. Pharmacological inhibition of LOX-1, or genetic ablation of Lox-1, reduces H. pylori colonization. Moreover, deletion of the bacterial catalase gene decreases adhesion of H. pylori to human gastric sections. Our results indicate that m⁶A modification of host LOX-1 mRNA contributes to protection against H. pylori infection by downregulating LOX-1 and thus reducing H. pylori adhesion.

MeSH terms

Adenosine* / analogs & derivatives
Animals
Catalase / metabolism
Helicobacter Infections* / metabolism
Helicobacter pylori* / metabolism
Humans
Mice
RNA, Messenger / genetics
Scavenger Receptors, Class E* / genetics

Substances

Adenosine
Catalase
N-methyladenosine
RNA, Messenger
Scavenger Receptors, Class E