UBE4A

更新于：2025-01-23

基本信息

别名

E4、KIAA0126、RING-type E3 ubiquitin transferase E4 A

+ [5]

简介

Ubiquitin-protein ligase that probably functions as an E3 ligase in conjunction with specific E1 and E2 ligases. May also function as an E4 ligase mediating the assembly of polyubiquitin chains on substrates ubiquitinated by another E3 ubiquitin ligase. Mediates 'Lys-48'-linked polyubiquitination of substrates.

关联

100 项与 UBE4A 相关的临床结果

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100 项与 UBE4A 相关的转化医学

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0 项与 UBE4A 相关的专利（医药）

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项与 UBE4A 相关的文献（医药）

2024-05-01·Clinics and Research in Hepatology and Gastroenterology

White adipose tissue in metabolic associated fatty liver disease

Review

作者: Yu, Baoping ; Zeng, Chuanfei ; Zhu, Xiaoqin

BACKGROUNDMetabolic associated fatty liver disease (MAFLD) is a prevalent chronic liver condition globally, currently lacking universally recognized therapeutic drugs, thereby increasing the risk of cirrhosis and hepatocellular carcinoma. Research has reported an association between white adipose tissue and MAFLD.SCOPE OF REVIEWWhite adipose tissue (WAT) is involved in lipid metabolism and can contribute to the progression of MAFLD by mediating insulin resistance, inflammation, exosomes, autophagy, and other processes. This review aims to elucidate the mechanisms through which WAT plays a role in the development of MAFLD.MAJOR CONCLUSIONSWAT participates in the occurrence and progression of MAFLD by mediating insulin resistance, inflammation, autophagy, and exosome secretion. Fibrosis and restricted expansion of adipose tissue can lead to the release of more free fatty acids (FFA), exacerbating the progression of MAFLD. WAT-secreted TNF-α and IL-1β, through the promotion of JNK/JKK/p38MAPK expression, interfere with insulin receptor serine and tyrosine phosphorylation, worsening insulin resistance. Adiponectin, by inhibiting the TLR-4-NF-κB pathway and suppressing M2 to M1 transformation, further inhibits the secretion of IL-6, IL-1β, and TNF-α, improving insulin resistance in MAFLD patients. Various gene expressions within WAT, such as MBPAT7, Nrf2, and Ube4A, can ameliorate insulin resistance in MAFLD patients. Autophagy-related gene Atg7 promotes the expression of fibrosis-related genes, worsening MAFLD. Non-pharmacological treatments, including diabetes-related medications and exercise, can improve MAFLD.

2023-09-01·Molecular Metabolism

Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo

Article

作者: Carlson, Haley L ; Chakraborty, Molee ; Jellinek, Matthew J ; Finck, Brian N ; Zhang, Jinsong ; Ford, David A ; Neuschwander-Tetri, Brent A ; Ulmasov, Barbara ; Haubner, Jake ; Lutkewitte, Andrew J ; Msengi, Eliwaza N ; Carpenter, Danielle ; McCommis, Kyle S ; Mukherjee, Sandip ; Pyles, Kelly ; Chakraborty, Anutosh

OBJECTIVEDefining the regulators of cell metabolism and signaling is essential to design new therapeutic strategies in obesity and NAFLD/NASH. E3 ubiquitin ligases control diverse cellular functions by ubiquitination-mediated regulation of protein targets, and thus their functional aberration is associated with many diseases. The E3 ligase Ube4A has been implicated in human obesity, inflammation, and cancer. However, its in vivo function is unknown, and no animal models are available to study this novel protein.METHODSA whole-body Ube4A knockout (UKO) mouse model was generated, and various metabolic parameters were compared in chow- and high fat diet (HFD)-fed WT and UKO mice, and in their liver, adipose tissue, and serum. Lipidomics and RNA-Seq studies were performed in the liver samples of HFD-fed WT and UKO mice. Proteomic studies were conducted to identify Ube4A's targets in metabolism. Furthermore, a mechanism by which Ube4A regulates metabolism was identified.RESULTSAlthough the body weight and composition of young, chow-fed WT and UKO mice are similar, the knockouts exhibit mild hyperinsulinemia and insulin resistance. HFD feeding substantially augments obesity, hyperinsulinemia, and insulin resistance in both sexes of UKO mice. HFD-fed white and brown adipose tissue depots of UKO mice have increased insulin resistance and inflammation and reduced energy metabolism. Moreover, Ube4A deletion exacerbates hepatic steatosis, inflammation, and liver injury in HFD-fed mice with increased lipid uptake and lipogenesis in hepatocytes. Acute insulin treatment resulted in impaired activation of the insulin effector protein kinase Akt in liver and adipose tissue of chow-fed UKO mice. We identified the Akt activator protein APPL1 as a Ube4A interactor. The K63-linked ubiquitination (K63-Ub) of Akt and APPL1, known to facilitate insulin-induced Akt activation, is impaired in UKO mice. Furthermore, Ube4A K63-ubiquitinates Akt in vitro.CONCLUSIONUbe4A is a novel regulator of obesity, insulin resistance, adipose tissue dysfunction and NAFLD, and preventing its downregulation may ameliorate these diseases.

2023-06-01·Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms

UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage

Article

作者: Cui, Meng-Ke ; Li, Zhao-Peng ; Zhang, Zaihui ; Zhang, Zai-Rong ; Li, Jiqiang ; Ji, Jia ; Ge, Man-Xi ; Hu, Xianyan ; Huo, Xin-Yu ; Wu, Ming-Zhi ; Zou, Rong ; Zhang, Xiaoli ; Wang, Qingchen ; Liu, Di

The transcription factor nuclear factor erythroid 2 like 1 (NFE2L1 or NRF1) regulates constitutive and inducible expression of proteasome subunits and assembly chaperones. The precursor of NRF1 is integrated into the endoplasmic reticulum (ER) and can be retrotranslocated from the ER to the cytosol where it is processed by ubiquitin-directed endoprotease DDI2. DDI2 cleaves and activates NRF1 only when NRF1 is highly polyubiquitinated. It remains unclear how retrotranslocated NRF1 is primed with large amount of ubiquitin and/or very long polyubiquitin chain for subsequent processing. Here, we report that E3 ligase UBE4A catalyzes ubiquitination of retrotranslocated NRF1 and promotes its cleavage. Depletion of UBE4A reduces the amount of ubiquitin modified on NRF1, shortens the average length of polyubiquitin chain, decreases NRF1 cleavage efficiency and causes accumulation of non-cleaved, inactivated NRF1. Expression of a UBE4A mutant lacking ligase activity impairs the cleavage, likely due to a dominant negative effect. UBE4A interacts with NRF1 and the recombinant UBE4A can promote ubiquitination of retrotranslocated NRF1 in vitro. In addition, knocking out UBE4A reduces transcription of proteasomal subunits in cells. Our results indicate that UBE4A primes NRF1 for DDI2-mediated activation to facilitate expression of proteasomal genes.

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