Protein ubiquitination is one of the essential protein post-translational modification (PTM) processes, which guided proteins in a cell for degradation in the proteasome. The dynamic balance between ubiquitination and de-ubiquitylation plays a key regulatory role in maintaining proteome homeostasis and the normal functions of a cell.

USP14 is the one of the major deubiquitinating enzymes (DUBs) bound to the proteasome, which is known to serve as a quality control component to rescue proteins from wrong degradation. Many studies have shown that USP14 plays critical roles in cellular signaling, neurological functions, and tumorigenesis. Inhibitors developed to target USP14 has shown promising potential for the treatment of various types of cancers. Nevertheless, an important unresolved question is whether there are unknown substrates of USP14 which could play important roles in cellular physiology or diseases.

In an article titled “Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN”, a research group led by Dr. TAN Minjia from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Dr. LI Xiaoying from Zhongshan Hospital of Fudan University, revealed new substrates and a new role of USP14 in non-alcoholic fatty liver disease(NAFLD), which is a major type of metabolic disorders and a severe public health problem worldwide. The findings were published in Nature Communications.

By carrying out large-scale quantitative profiling for proteome, ubiquitinome and protein interactome of USP14, they revealed various new cellular pathways that USP14 likely participates in, especially energy metabolism. Using various biochemical methods, they further demonstrated fatty acid synthase (FASN), a key enzyme involved in fatty acid synthesis, was a new direct substrate of USP14. Additional genetic and biochemical experiment at cellular and mouse models showed that USP14-mediated deubiquitination and stabilization of FASN promotes triglyceride accumulation in liver.

These studies revealed a new mechanism of NAFLD, suggested that USP14 could be a potential new target for therapeutic treatment of NAFLD.

This study was supported by the National Key Research and Development Program of China, National Basic Research Program of China (973 Program), the Natural Science Foundation of China, the Special Project on Precision Medicine under the National Key R&D Program, the Innovation Project of Instrument and Equipment Function Development of the Chinese Academy of Sciences, Shanghai Rising-Star Program by Science and Technology Commission of Shanghai Municipality and K. C. Wong Education Foundation.

Link to the article: https://www.nature.com/articles/s41467-018-07185-y

A model of USP14 in non-alcoholic fatty liver disease (Image by Dr. TAN Minjia’s Lab)

Contact:
Prof. TAN Minjia
Email: mjtan@simm.ac.cn

(Credit: TAN Minjia; Edior: PAN Peihua)