Sumoylation in liver disease

The small ubiquitin-like modifier (SUMO) family is a highly conserved post-translational modified protein found in eukaryotes. Currently, at least five SUMO isoforms have been found, including SUMO1, SUMO2, SUMO3, SUMO4 and SUMO5.Among them, SUMO2 is highly homologous to SUMO3, which is currently not distinguishable by antibodies and are commonly known as SUMO-2/3. Morever, SUMO1 and SUMO-2/3 share 50% sequence homology, Nevertheless, they show obvious differences in self-activation, binding and function.

The SUMO-2/3 binding pathway is a reversible protein modification that occurs under heat shock, but the SUMO1 binding pathway has no significant changes, suggesting that the SUMO-2/3 binding pathway may have a more significant effect on cellular stress response feature.SUMO4 is encoded by a sequence found within an intro of the human TAB2 gene, which is highly expressed in the kidney, spleen and lymph nodes.

Additionally, SUMO4 has a unique polymorphic gene, M55v, which may be associated with the pathogenesis of diabetes. Recently, SUMO5 was identified as a novel member of the SUMO family,and is more highly expressed in testes and peripheral hemolymph, though it has lower expression in the lungs and liver. In general, there are two main proteolytic systems in eukaryotic cells: the ubiquitin-proteasome system (UPS) and autophagy.

The ubiquitin cycle mainly enables the target protein to be recognized and degraded by the proteasome. As a member of UPS, but the SUMO cycle is functionally different from the ubiquitin cycle. The SUMO cycle regulates protein-protein interactions, mediating the localization and function of target proteins.

SUMOylation is the covalent modification of SUMO to substrates and encompass a global change of the SUMO proteome. All SUMO proteins undergo the same enzymatic catalysis of binding and dissociating with the substrate. SUMOylation is achieved through the cooperation action of three enzymes: ubiquitin-activating enzyme (E1), ubiquitin-transferring enzyme (E2), and ubiquitin ligase (E3). Specifically, the E1 activating enzyme forms thioesters between the active cysteine of SUMO and Uba2 in an ATP-dependent manner and subsequently transfers to the E2 binding enzyme in order to form E2-SUMO thioesters.

Accordingly, the E3 ligase recruits E2-SUMO thioesters and substrates to form complexes to increase specificity.However, the E2 enzyme can specifically recognize SUMO and bind it to the substrate without action of the E3 ligase. As previously mentioned, SUMOylation sever as a common and vital post-translational modification.

In which its target protein is mainly nuclear proteins. SUMOylation can act on different tissues and involves in many cellular processes such as DNA repair, transcriptional regulation, protein stabilization, and cell cycle progression. Moreover, as a dynamic and reversible process, SUMOylation is regulated by a series of proteases that can remove SUMO protein from substrates.

The functions of SUMOylation on human diseases

Accumulating evidence has shown that the imbalance between SUMOylation and deSUMOylation or alterations in its components, engenders various pathological changes. Indeed, the deregulation of either SUMO conjugation or deconjugation can affect tumor proliferation and migration.

In detail, SUMO1 can specifically bind to Lys6 and Lys63 of the peptidyl-prolyl cis/trans isomerase (PPIase) Pin1, which is a unique prolyl isomerase that inhibits the substrate binding ability, phospho-specific PPIase activity and cellular function. SENP1 was also found to reverse the SUMOylation of Pin1 and promote human breast cancer cell proliferation and tumorigenesis.

Besides, overexpressed SUMO1 accelerates the proliferation and migration of non-small cell lung cancer by promoting NF-κB expression. SUMO also serves as a target for cancer treatment. Melatonin inhibits SUMO1 to reduce the nuclear translocation of Nestin binding to c-Myc, and decreases Nestin and c-Myc in XO2 cells, inhibiting stemness.

Additionally, SUMOylation plays a crucial role in viral infection. Specifically, it provides a host defense mechanism by eliminating viral components and blocking the virus life cycle. However, viruses utilize components of SUMOylation in order to maintain viral protein levels and promote viral replication.

The roles of SUMOylation in liver diseases

Importantly, a growing number of studies indicate that SUMOylation is closely related to the progression of liver diseases. Particularly, Ran-binding protein 2(RanBP2) promotes SUMO2 modification of Small Heterodimer Partner (SHP), and the SUMOylation of SHP can inhibit bile acid (BA) synthetic genes by promoting the interaction with repressive histone-modifying enzymes, thereby reducing cholestasis and liver damage caused by abnormal bile accumulation.

In addition, SUMO1 can promote the metastasis and invasion of hepatocellular carcinoma (HCC) and promote Hepatitis C virus (HCV) replication. Altogether, the obtained results illustrate that SUMOylation is closely correlated to the development of liver diseases. Hence, the specific roles of SUMOylation in liver diseases are reviewed herein.

SUMOylation accelerates the progression of HCC acting as a new target for treatment

HCC, a common deadly disease, is the major type of primary liver cancer and is caused by multiple factors. A plethora of evidence has highlighted the roles of the SUMOylation in tumorigenesis. Intriguingly, SUMO1 expression is upregulated in HCC cells and is relevant to the multidrug resistance of HCC.

Moreover, SUMO1 facilitates the metastasis and invasion of liver cancer cells, thereby promoting the progression of HCC. However, SUMO1 also enhances p53-induced hepatocyte cell apoptosis. Overall, SUMO1-mediated SUMOylation is intimately related to hepatocarcinogenesis as well as the metastasis of HCC.

Furthermore, small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3) is a novel identified lncRNA, which is upregulated in HCC. Inhibition of SUMO1P3 significantly prevents the proliferation and migration of HCC, which promotes apoptosis and enhances the radiosensitivity of HCC cells. Liver Kinase B1 (LKB1) functions as an activator of the APK(AMP-activated protein kinase-related kinase) family including AMP-activated protein kinase(AMPK), AMPK acts as a cell energy sensor, which inhibits the mammalian target of the rapamycin complex 1(mTORC1) pathway.

Also, AMPK blocks the aerobic glycolysis pathway during hypoxia, providing energy for tumor cells. LKB1 has two special nuclear localization sequences that allow it to undergo nuclear transport. The nucleocytoplasmic shuttling of LKB1 is mainly mediated by STRADα. And MO25 can stabilize the interaction between the STRADα and LKB1.

SUMOylation promotes hepatitis virus replication

Overall, ample evidence has demonstrate that viruses interact with SUMO. Similar to the advantages of the intracellular SUMOylation protein, the substrate of most SUMOylation viruses is the nucleoprotein of DNA viruses or retroviruses.

Regarding DNA viruses, all of the known SUMOylated viral proteins are immediate-early or early nuclear proteins. Viral hepatitis is an infectious disease, and its incidence has continued to increase in recent years, affecting the health of most people in the world. Among them, Hepatitis B, Hepatitis C and Hepatitis D can present asymptomatically and lead to chronic carriers,which may further develop into cirrhosis and liver cancer.

Hepatitis B virus (HBV) , a member of the Hepadnaviridae family, is a double-stranded DNA virus. HBV has four overlapping open reading frames (ORFs) that encode viral envelope proteins, viral polymerase, the core protein, HBe antigen and non-structural protein hepatitis B virus X protein (HBX). HBX interacts with PML-NB protein Speckled 110kDa (SP110), which promotes deSUMOylation of SP110 and drives its exiting from Promyelocytic leukemia nuclear bodies (PML-NB), promoting virus replication.

In HBV-infected hepatocytes, SENP3 expression is downregulated, and its deficiency can promote the degradation of IQ motif containing GTPase activating protein 2 (IQGAP2) modified by SUMO-2/3 and facilitate AKT phosphorylation. Subsequently, the activated AKT and PI3K/AKT signaling pathway reduces HBV transcription and replication through hepatocyte nuclear factor 4α (HNF4α) restoring the host’s translation activity.

SUMOylation is involved in non-alcoholic fatty liver disease and liver fibrosis

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent metabolic disease. The classic multiple-hit theory redarding the pathogenesis of NAFLD posits that lipid accumulation result in steatosis and triggers multiple injuries, ultimately causing liver cancer and cirrhosis. Disruption of the balance between lipid production and lipolysis leads to lipid accumulation.

Sterol regulatory element-binding protein (SREBP1c) is a key transcription factor in cholesterol and lipid homeostasis. SREBP1c modified by SUMO1 can repress the transcriptional activity of SREBP1c and inhibits lipid production. The mammalian protein inhibitor of activated STAT (PIAS) protein is a representative SUMO E3 ligase and contains four members: PISA1, PIAS2, PIAS3, and PIASy.

PIASy can promote the SUMOylation of SREBP1c and reduce lipid production in the absence of nutrition. Furthermore, knockout of SENP1 inhibits the expression of CCAAT/enhance-binding protein (C/EBPα / β) and peroxisome proliferator-activated receptor γ (PPARγ), the major regulators and transcriptional factors of lipid production, thus reducing the adipocyte differentiation. Additionally SUMOylation of sharp-1 can repress the formation of lipid droplets.

 

Author: Min Zeng, Wenhui Liu, Yang Hu, Nian Fu

 

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