Hepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice

Cheng Xu, Hongyi Zhou, Yulan Jin, Khushboo Sahay, Anna Robicsek, Yisong Liu, Kunzhe Dong, Jiliang Zhou, Amanda Barrett, Huabo Su and Weiqin Chen ()
Additional contact information
Cheng Xu: Medical College of Georgia at Augusta University
Hongyi Zhou: Medical College of Georgia at Augusta University
Yulan Jin: Medical College of Georgia at Augusta University
Khushboo Sahay: Medical College of Georgia at Augusta University
Anna Robicsek: Medical College of Georgia at Augusta University
Yisong Liu: Medical College of Georgia at Augusta University
Kunzhe Dong: Medical College of Georgia at Augusta University
Jiliang Zhou: Medical College of Georgia at Augusta University
Amanda Barrett: Medical College of Georgia at Augusta University
Huabo Su: Medical College of Georgia at Augusta University
Weiqin Chen: Medical College of Georgia at Augusta University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract The conjugation of neural precursor cell expressed, developmentally downregulated 8 (NEDD8) to target proteins, termed neddylation, participates in many cellular processes and is aberrant in various pathological diseases. Its relevance to liver function and failure remains poorly understood. Herein, we show dysregulated expression of NAE1, a regulatory subunit of the only NEDD8 E1 enzyme, in human acute liver failure. Embryonic- and adult-onset deletion of NAE1 in hepatocytes causes hepatocyte death, inflammation, and fibrosis, culminating in fatal liver injury in mice. Hepatic neddylation deficiency triggers oxidative stress, mitochondrial dysfunction, and hepatocyte reprogramming, potentiating liver injury. Importantly, NF-κB-inducing kinase (NIK), a serine/Thr kinase, is a neddylation substrate. Neddylation of NIK promotes its ubiquitination and degradation. Inhibition of neddylation conversely causes aberrant NIK activation, accentuating hepatocyte damage and inflammation. Administration of N-acetylcysteine, a glutathione surrogate and antioxidant, mitigates liver failure caused by hepatic NAE1 deletion in adult male mice. Therefore, hepatic neddylation is important in maintaining postnatal and adult liver homeostasis, and the identified neddylation targets/pathways provide insights into therapeutically intervening acute liver failure.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-35525-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35525-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-35525-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().