Palmitoylation of NOD1 and NOD2 is required for bacterial sensing

Science. 2019 Oct 25;366(6464):460-467. doi: 10.1126/science.aau6391.

Yan Lu ^# ¹ ², Yuping Zheng ^# ¹, Étienne Coyaud ^# ³, Chao Zhang ^# ⁴ ⁵, Apiraam Selvabaskaran ⁶, Yuyun Yu ¹, Zizhen Xu ¹, Xialian Weng ¹, Ji Shun Chen ¹, Ying Meng ¹, Neil Warner ⁷, Xiawei Cheng ⁸, Yangyang Liu ⁹, Bingpeng Yao ¹⁰, Hu Hu ⁹, Zonping Xia ¹¹, Aleixo M Muise ⁷, Amira Klip ¹², John H Brumell ⁷ ¹³, Stephen E Girardin ⁶, Songmin Ying ¹⁰, Gregory D Fairn ¹⁴, Brian Raught ¹⁵ ¹⁶, Qiming Sun ¹⁷, Dante Neculai ¹⁸

Affiliations

1 Department of Cell Biology, and Department of Pathology Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2 Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, Toronto, ON, Canada.
3 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
4 Department of Anatomy, School of Medicine, Zhejiang University, China School of Medicine, Zhejiang University, Hangzhou 310058, China.
5 Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
6 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
7 SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.
8 Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
9 Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
10 Department of Pharmacology and Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Institute of Respiratory Diseases, Zhejiang University School of Medicine, Hangzhou 310009, China.
11 Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
12 Cell Biology Program, Research Institute, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning (PGCRL), Toronto, ON, Canada.
13 Department of Molecular Genetics and Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
14 Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, Toronto, ON, Canada. greg.fairn@unityhealth.to brian.raught@uhnresearch.ca qmsun@zju.edu.cn dneculai@zju.edu.cn.
15 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. greg.fairn@unityhealth.to brian.raught@uhnresearch.ca qmsun@zju.edu.cn dneculai@zju.edu.cn.
16 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
17 Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. greg.fairn@unityhealth.to brian.raught@uhnresearch.ca qmsun@zju.edu.cn dneculai@zju.edu.cn.
18 Department of Cell Biology, and Department of Pathology Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. greg.fairn@unityhealth.to brian.raught@uhnresearch.ca qmsun@zju.edu.cn dneculai@zju.edu.cn.
# Contributed equally.

PMID: 31649195 DOI: 10.1126/science.aau6391

Abstract

The nucleotide oligomerization domain (NOD)-like receptors 1 and 2 (NOD1/2) are intracellular pattern-recognition proteins that activate immune signaling pathways in response to peptidoglycans associated with Microorganisms. Recruitment to bacteria-containing endosomes and other intracellular membranes is required for NOD1/2 signaling, and NOD1/2 mutations that disrupt membrane localization are associated with inflammatory bowel disease and other inflammatory conditions. However, little is known about this recruitment process. We found that NOD1/2 S-palmitoylation is required for membrane recruitment and immune signaling. ZDHHC5 was identified as the palmitoyltransferase responsible for this critical posttranslational modification, and several disease-associated mutations in NOD2 were found to be associated with defective S-palmitoylation. Thus, ZDHHC5-mediated S-palmitoylation of NOD1/2 is critical for their ability to respond to peptidoglycans and to mount an effective immune response.

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