E3 ubiquitin ligases as novel targets for inflammatory diseases

Goru, Santosh Kumar; Pandey, Anuradha; Gaikwad, Anil Bhanudas

doi:10.1016/j.phrs.2016.02.006

Cited by 31 publications

(26 citation statements)

References 88 publications

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“…23 RING E3 ubiquitin ligases regulate inflammation. 24 They are also critical regulators of TLRs pathways. Depletion of Casitas B-lineage lymphoma-b (Cbl-b), a RING E3 ubiquitin ligase, promotes IL-6 expression in saturated fatty acids-induced peritoneal macrophages through TLR4-mediated JNK/NF- κ B pathway 25 and induces pro-inflammatory cytokine TNF- α , MCP-1 and IL-6 secretion in bone marrow-derived cultured mast cells (BMMCs).…”

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confidence: 99%

Ubiquitylation of MFHAS1 by the ubiquitin ligase praja2 promotes M1 macrophage polarization by activating JNK and p38 pathways

et al. 2017

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Sepsis is a systemic inflammation caused by infection. The balance between M1–M2 macrophage polarization has an essential role in the pathogenesis of sepsis. However, the exact mechanism underlying macrophage polarization is unclear. We previously showed that levels of malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) were significantly elevated in septic patients compared with those in nonseptic patients, and involved in the activation of Toll-like receptor (TLR) 2/c-Jun N-terminal kinase (JNK)/nuclear factor (NF)-κB pathway. In the present study, we explored whether MFHAS1 was involved in macrophage polarization and determined the effect of MFHAS1 on inflammation. We performed in vitro pulldown assays and in vivo co-immunoprecipitation assays and found that E3 ubiquitin ligase praja2 could directly bind to MFHAS1. In situ immunostaining analysis confirmed the colocalization of endogenous praja2 with MFHAS1. We first reported that praja2 promotes the accumulation of ubiquitylated MFHAS1 but does not degrade it. Moreover, our results indicate that MFHAS1 ubiquitylation by praja2 positively regulates TLR2-mediated JNK/p38 pathway and promotes M1 macrophage polarization, M2 to M1 macrophage transformation and inflammation.

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Ubiquitylation of MFHAS1 by the ubiquitin ligase praja2 promotes M1 macrophage polarization by activating JNK and p38 pathways

et al. 2017

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“…The ubiquitin proteasome pathway is the predominant protein degradation pathway, 8 and its activation is regulated by various proteins, such as gp78. 9 This protein also forms a specialized tubule between the closely adjacent endoplasmic reticulum and mitochondria, and facilitates the rapid transfer of calcium from the former to the latter.…”

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confidence: 99%

Calcium sensing receptor protects high glucose-induced energy metabolism disorder via blocking gp78-ubiquitin proteasome pathway

et al. 2017

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Diabetic cardiomyopathy (DCM) is a major complication and fatal cause of the patients with diabetes. The calcium sensing receptor (CaSR) is a G protein-coupled receptor, which is involved in maintaining calcium homeostasis, regulating cell proliferation and apoptosis, and so on. In our previous study, we found that CaSR expression, intracellular calcium levels and cardiac function were all significantly decreased in DCM rats; however, the exact mechanism are not clear yet. The present study revealed the protective role of CaSR in myocardial energy metabolism disorder induced by high glucose (HG) as well as the underlying mechanism. Here, we demonstrated that HG decreased the expression of CaSR, mitochondrial fusion proteins (Mfn1, Mfn2), cell gap junction related proteins (Cx43, β-catenin, N-cadherin), and intracellular ATP concentration. In contrast, HG increased extracellular ATP concentration, the expression of gp78, mitochondrial fission proteins (Fis1, Drp1), and the ubiquitination levels of Mfn1, Mfn2 and Cx43. Moreover, CaSR agonist and gp78-siRNA significantly reduced the above changes. Taken together, these results suggest that HG induces myocardial energy metabolism disorder via decrease of CaSR expression, and activation of gp78-ubiquitin proteasome system. In turn, these effects disrupt the structure and function of the mitochondria and the cell gap junction, result in the reduced ATP synthesis and the increased ATP leakage. Stimulation of CaSR significantly attenuates HG-induced abnormal myocardial energy metabolism, suggesting CaSR would be a promising potential therapeutic target for DCM.

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“…As a result, targeting these enzymes may offer opportunities for fine-tuning inflammatory signaling processes for therapeutic benefits in infectious diseases and metabolic, autoimmune and autoinflammatory disorders. 52, 53 …”

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confidence: 99%

Post-translational regulation of inflammasomes

2016

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Inflammasomes play essential roles in immune protection against microbial infections. However, excessive inflammation is implicated in various human diseases, including autoinflammatory syndromes, diabetes, multiple sclerosis, cardiovascular disorders and neurodegenerative diseases. Therefore, precise regulation of inflammasome activities is critical for adequate immune protection while limiting collateral tissue damage. In this review, we focus on the emerging roles of post-translational modifications (PTMs) that regulate activation of the NLRP3, NLRP1, NLRC4, AIM2 and IFI16 inflammasomes. We anticipate that these types of PTMs will be identified in other types of and less well-characterized inflammasomes. Because these highly diverse and versatile PTMs shape distinct inflammatory responses in response to infections and tissue damage, targeting the enzymes involved in these PTMs will undoubtedly offer opportunities for precise modulation of inflammasome activities under various pathophysiological conditions.

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E3 ubiquitin ligases as novel targets for inflammatory diseases

Cited by 31 publications

References 88 publications

Ubiquitylation of MFHAS1 by the ubiquitin ligase praja2 promotes M1 macrophage polarization by activating JNK and p38 pathways

Ubiquitylation of MFHAS1 by the ubiquitin ligase praja2 promotes M1 macrophage polarization by activating JNK and p38 pathways

Calcium sensing receptor protects high glucose-induced energy metabolism disorder via blocking gp78-ubiquitin proteasome pathway

Post-translational regulation of inflammasomes

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