Progress of Small Ubiquitin-Related Modifiers in Kidney Diseases
Small ubiquitin-related modifiers (SUMOs) are a group of post-translational modification proteins extensively expressed in eukaryotes. These proteins play a crucial role in various cellular processes, including transcriptional regulation, DNA repair, protein stability, cell proliferation, and apoptosis. Abnormal SUMOylation, the process by which SUMO proteins are conjugated to target proteins, can lead to the development of various diseases, including kidney diseases. This article provides a comprehensive review of the role of SUMOs in different types of kidney diseases, highlighting their regulatory functions in the pathogenesis of these conditions.
Introduction to SUMOs
SUMOs are a family of highly conserved post-translational modification proteins in eukaryotes. The SUMO family includes four members in mammalian cells: SUMO-1, SUMO-2, SUMO-3, and SUMO-4. SUMO-1, with a molecular weight of 11,600, is composed of 101 amino acids. SUMO-2 and SUMO-3 share 95% homology in their amino acid sequences and are distinguished by only three N-terminal amino acid residues. These two proteins share approximately 45% homology with SUMO-1. SUMO-4, on the other hand, exhibits low expression levels under physiological conditions and is primarily involved in cellular responses to oxidative stress and hypoxic injury.
The process of SUMOylation involves a series of enzymatic reactions. First, SUMO-specific proteases (SENPs) cleave several C-terminal amino acids of SUMOs to expose diglycine residues, resulting in mature SUMOs. These mature SUMOs are then activated by E1 activating enzymes (SAE1 and SAE2) in an ATP-dependent manner. The activated SUMOs are subsequently transferred to the E2 conjugating enzyme Ubc9, which recognizes the conserved sequence C-K-x-D/E on the substrate protein. Finally, under the catalytic function of E3 ligases (PIAS1, PIASx, PIAS3, PIASy, RanBP2, and Pc2), SUMOs are conjugated to lysine residues of the substrate proteins, forming isopeptide bonds. This process can be reversed through de-SUMOylation, where SENPs dissociate SUMOs from the substrate proteins.
SUMOs and Acute Kidney Injury (AKI)
Acute kidney injury (AKI) is a clinical syndrome characterized by acute injury and necrosis of tubular cells, leading to abnormal kidney function and structure. The mortality rate for AKI is high, often exceeding 50%. The common etiologies of AKI include prerenal injury due to hypertension and heart failure, renal injury induced by infection and renal parenchyma, and postrenal injury caused by urethral obstruction.
Research has shown that SUMOylation plays a protective role in AKI. In an ischemia/reperfusion-induced AKI mouse model, the level of ATP-dependent SUMOylation significantly decreases during ischemic injury due to the depletion of cellular ATP. However, this level can be restored after tissue reperfusion. In cisplatin-induced AKI, oxidative stress promotes the generation of disulfide bonds between molecules, inactivating SUMO proteases and enhancing SUMOylation in cells. Moderate oxidative stress, on the other hand, can induce cysteine residues of E1s and E2s to form disulfide bonds, stabilizing the activity of SUMO proteases and inhibiting the SUMOylation process.
In a cisplatin-induced tubular cell experiment, the use of the p53 inhibitor PFT-α blocked the conjugation of SUMO-2/3, inhibiting SUMOylation and reducing apoptosis. Similarly, ginkgolic acid, a SUMOylation inhibitor, can block the binding between SUMOs and E1s, inhibiting SUMOylation and resisting apoptosis. SUMOylation of the mitochondrial fission protein Drp1 can block its accumulation in mitochondria, preventing mitochondrial fission, cytochrome C release, and apoptosis. SUMO-2/3 can bind to nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), inducing SUMOylation and blocking its dissociation from nuclear factor-κB (NF-κB), thus inhibiting NF-κB activation and promoting cell survival. SUMO-1 can bind to histone deacetylase 2 (HDAC2), inducing SUMOylation and causing deacetylation of p53, blocking the activation of apoptotic genes and reducing DNA damage-induced apoptosis.
SUMOs and Diabetic Nephropathy (DN)
Diabetic nephropathy (DN) is a common complication of diabetes mellitus, characterized by microvascular lesions. The pathological process of DN involves multiple signaling pathways, including the transforming growth factor beta (TGF-β) pathway, NF-κB pathway, and mitogen-activated protein kinase (MAPK) pathway.
SUMOylation plays a significant role in the progression of DN through the regulation of these signaling pathways. In the NF-κB pathway, SUMO-1 binds to the K21 and K22 sites of IκBα under the catalytic function of Ubc9, preventing its degradation by ubiquitination and further inhibiting NF-κB activation. SUMO-4 primarily participates in the regulation of the NF-κB signaling pathway in glomerular cells, while SUMO-2 and SUMO-3 mediate NF-κB activation under high-glucose conditions. The SUMOylation of NEMO, involving SUMO-1, mainly regulates NF-κB activation during genotoxic reactions. RelA, another subunit of NF-κB, can undergo SUMOylation mediated by PIAS3 to inhibit NF-κB activation.
In the MAPK pathway, de-SUMOylation of the transcription factor Elk1 can activate the ERK pathway. SUMOs can bind to the central group of ERK5, inhibiting its transcriptional activity and participating in the regulatory process of endothelial cell dysfunction caused by diabetes mellitus. PIAS mediates SUMOylation of tissue transglutaminase (TG2), inhibiting TG2 degradation by ubiquitination and maintaining the biological activity of TG2, thus promoting cellular oxidative stress and chronic inflammatory responses.
Podocytes, essential for maintaining the function of the glomerular filtration barrier, are also affected by SUMOylation. Research has shown that nephrin, a substrate modified by SUMO proteins, plays a crucial role in maintaining the normal function of podocytes. The conversion of lysine at position 1100 of nephrin decreases its stability and expression at the plasma membrane. SENP1 deficiency significantly increases the apoptosis of podocytes induced by puromycin aminonucleoside (PAN). SENP1 knockdown results in the SUMOylation of p53 protein, increasing the expression of p53-targeted genes such as HI, BAX, NOXA, and PUMA in podocytes. Hypoxia blocks the proteasome degradation of hypoxia-inducible factor (HIF-1) in the cytoplasm and induces nuclear translocation and SUMOylation of HIF-1 in podocytes. SENP1 allows HIF-1 to escape degradation and remain stable in the nucleus, promoting the transcription of the downstream gene VEGF in hypoxia.
SUMOs and Renal Fibrosis Diseases
Renal fibrosis is characterized by glomerular and interstitial inflammatory cell infiltration and matrix deposition, leading to glomerular sclerosis and interstitial fibrosis. The TGF-β/Smad pathway plays a central role in the process of renal fibrosis.
SUMOylation of the Smad protein in the TGF-β pathway inhibits its transcriptional activation, while TGF-β receptor SUMOylation can promote binding to its ligands, activating signaling pathways. SUMOylated Smad3 acts on PIASy to inhibit the TGF-β pathway. Smad4 can bind to SUMO-1, inducing SUMOylation, increasing its stability, and promoting transcriptional activation. SUMOylation of TGF-β receptor 1 (TbRI) increases its ligand recruitment ability and the phosphorylation level of Smad3, further enhancing receptor functions, promoting transcriptional activation of TGF-β, and inhibiting proliferation.
The proto-oncogenes c-Ski and SnoN inhibit the anti-proliferation function of TGF-β through interaction with Smads. SUMO-1 can bind to the K50 site of SnoN, inducing SUMOylation under the catalysis of PIAS1 and PIASx, while Arkadia can activate the TGF-β pathway through the degradation of SnoN/Ski.
SUMOs and Renal Cell Carcinoma
SUMOs are involved in the process of tumor formation by modifying various oncogenes and tumor suppressor genes, influencing signal transduction pathways involved in the cell cycle, proliferation, and apoptosis.
Epidemiological studies have shown that melanoma patients are prone to subsequent renal cell carcinoma. The microphthalmia-associated transcription factor (MITF) plays an important role in the maintenance of melanocyte growth and differentiation and melanoma development. The missense substitution mutation Mi-E318K in MITF blocks SUMOylation, promoting ubiquitin-mediated MITF degradation and tumor development. MITF (Mi-E318K) can activate the transcription of the hypoxia-inducible factor HIF-1A, increasing the ability of tumors to tolerate hypoxia and promoting tumor proliferation.
Von Hippel-Lindau (VHL) syndrome, an autosomal dominant hereditary disease, involves multiple organ lesions caused by mutations in the tumor suppressor gene VHL. SUMO-1 and SUMO-2 bind to the K171 site of pVHL, inducing SUMOylation and inhibiting pVHL degradation. The RWDD3 gene-encoded product RWD domain-containing protein SUMO Enhancer (RSUME) promotes SUMOylation of pVHL, blocking its binding to Elongins and Cullins (ECV) to form the ubiquitin-proteasome complex, thus inhibiting HIF-1 degradation and promoting tumor development.
Discussion and Perspective
SUMOylation is a crucial post-translational modification that regulates protein stability, interaction, localization, and activation. It plays a significant role in various cellular processes, including signal transduction, nuclear transport, transcriptional regulation, and genetic integrity. In kidney diseases, SUMOylation is involved in tissue injury, inflammatory responses, fibrosis, apoptosis, and tumor proliferation.
The relationship between SUMOylation and autophagy is also of interest. Autophagy is a conserved pathway that degrades and recycles damaged organelles to maintain intracellular homeostasis. The autophagy pathway is upregulated under stress conditions, including cell starvation, hypoxia injury, nutrient deprivation, endoplasmic reticulum stress, and oxidant stress, which are involved in the pathogenesis of kidney disease. SUMOylation may contribute to the autophagy mechanism of kidney disease.
SUMOylation also plays a key role in nutrient and metabolic mechanisms that influence cellular metabolism. There is increasing evidence that SUMO is a key component of the regulation of fundamental metabolic processes, including energy and nucleotide metabolism. Further research is needed to understand the relationship between SUMO and metabolism in the kidney’s physiological and pathological environment.
Although few studies have examined the treatment of kidney disease using SUMOylation, some research indicates that SENPs and SUMO inhibitors may be applied in targeted therapy of kidney tumors. With the development of SUMOylation and the discovery of novel SUMO inhibitors, new therapeutic methods and strategies based on SUMOylation will be discovered in the near future.
Conclusions
In summary, SUMOylation is an indispensable process by which proteins participate in life-sustaining activities. The dynamic balance between SUMOylation and ubiquitination regulates the expression of signaling molecules in various physiological and pathological processes to maintain normal cellular functions. Abnormal SUMOylation or de-SUMOylation processes directly result in changes in the expression of corresponding substrate proteins, activating signaling pathways and inducing a series of pathological responses that eventually cause the development of various diseases.
In kidney diseases, SUMOylation plays a crucial role in tissue injury, inflammatory responses, fibrosis, apoptosis, and tumor proliferation. Further research on substrate SUMOylation and the regulatory mechanisms of SUMO in kidney diseases will improve and develop new treatment measures and strategies targeting these conditions.
doi.org/10.1097/CM9.0000000000000094
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