HDAC6‐mediated α‐tubulin deacetylation suppresses autophagy and enhances motility of podocytes in diabetic nephropathy

Liang, Tiantian; Qi, Chunfang; Lai, Yuxiong; Xie, Jianteng; Wang, Huizhen; Zhang, Li; Lin, Tzu Chen; Jv, Menglei; Li, Jing; Wang, Yanhui; Zhang, Yifan; Chen, Zujiao; Qiu, Xueqian; Li, Ruizhao; Li, Zhilian; Ye, Zhiming; Liu, Shuangxin; Liang, Xinling; Shi, Wei; Wang, Wenjian

doi:10.1111/jcmm.15772

Cited by 18 publications

(19 citation statements)

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“…The fusion of autophagosomes with lysosomes was regulated by microtubule stabilization, which was modulated by histone deacetylase 6 (HDAC6)–induced α-tubulin deacetylation ( 29 , 30 ); thus, the structure and acetylation of α-tubulin, as well as HDAC6 activity, were examined to evaluate the stability of microtubules ( 31 , 32 ). The results showed that chondrocytes in the calcified group exhibited disordered and decreased α-tubulin expression ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Autophagic LC3 ⁺ calcified extracellular vesicles initiate cartilage calcification in osteoarthritis

et al. 2022

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Pathological cartilage calcification plays an important role in osteoarthritis progression but in which the origin of calcified extracellular vesicles (EVs) and their effects remain unknown. Here, we demonstrate that pathological cartilage calcification occurs in the early stage of the osteoarthritis in which the calcified EVs are closely involved. Autophagosomes carrying the minerals are released in EVs, and calcification is induced by those autophagy-regulated calcified EVs. Autophagy-derived microtubule-associated proteins 1A/1B light chain 3B (LC3)–positive EVs are the major population of calcified EVs that initiate pathological calcification. Release of LC3-positive calcified EVs is caused by blockage of the autophagy flux resulted from histone deacetylase 6 (HDAC6)–mediated microtubule destabilization. Inhibition of HDAC6 activity blocks the release of the LC3-positive calcified EVs by chondrocytes and effectively reverses the pathological calcification and degradation of cartilage. The present work discovers that calcified EVs derived from autophagosomes initiate pathological cartilage calcification in osteoarthritis, with potential therapeutic targeting implication.

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Section: Resultsmentioning

confidence: 99%

Autophagic LC3 ⁺ calcified extracellular vesicles initiate cartilage calcification in osteoarthritis

et al. 2022

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“…The possible underlying mechanism is that acetylation of a-tubulin enhances the endoplasmic reticulum-mitochondria contact, which promotes the formation of autophagosomes (82,83). Additionally, other studies have reported that HDAC6 mediates a-tubulin deacetylation to suppress autophagy in podocytes and human embryonic kidney 293 cells (84,85). However, the underlying mechanisms remain unclear.…”

Section: Hdac6 Deacetylates A-tubulin and Cortactin To Mediate Autophagymentioning

confidence: 99%

The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

Chang

et al. 2021

Front. Immunol.

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Autophagy fights against harmful stimuli and degrades cytosolic macromolecules, organelles, and intracellular pathogens. Autophagy dysfunction is associated with many diseases, including infectious and inflammatory diseases. Recent studies have identified the critical role of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes activation in the innate immune system, which mediates the secretion of proinflammatory cytokines IL-1β/IL-18 and cleaves Gasdermin D to induce pyroptosis in response to pathogenic and sterile stimuli. Accumulating evidence has highlighted the crosstalk between autophagy and NLRP3 inflammasome in multifaceted ways to influence host defense and inflammation. However, the underlying mechanisms require further clarification. Histone deacetylase 6 (HDAC6) is a class IIb deacetylase among the 18 mammalian HDACs, which mainly localizes in the cytoplasm. It is involved in two functional deacetylase domains and a ubiquitin-binding zinc finger domain (ZnF-BUZ). Due to its unique structure, HDAC6 regulates various physiological processes, including autophagy and NLRP3 inflammasome, and may play a role in the crosstalk between them. In this review, we provide insight into the mechanisms by which HDAC6 regulates autophagy and NLRP3 inflammasome and we explored the possibility and challenges of HDAC6 in the crosstalk between autophagy and NLRP3 inflammasome. Finally, we discuss HDAC6 inhibitors as a potential therapeutic approach targeting either autophagy or NLRP3 inflammasome as an anti-inflammatory strategy, although further clarification is required regarding their crosstalk.

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“…Bufexamac, an aryl alkanoic acid derivative and a nonsteroidal anti-inflammatory agent for the topical treatment of eczema and other inflammatory skin diseases [ 56 ], is a specific inhibitor of the deacetylases of histone types IIB (HDAC6 and HDAC10 [ 57 ]). Liang et al [ 58 ] proved that HDAC6, a kind of histone deacetylase (HDAC), downregulated the acetylation of α -tubulin, heightened motility, and restrained autophagy in podocytes dealing with AGE, which deteriorated the phenotype of DN, suggesting that HDAC6 is a prospective target for therapy in the early phase of DN. In addition, growing data suggest that the inhibition of HDAC can ameliorate clinical manifestations of diabetic kidney disease and phenotypes such as fibrosis, inflammation, cell death, and albuminuria [ 59 – 61 ].…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Multiple Microarray Studies to Identify Core Gene-Expression Signatures Involved in Tubulointerstitial Injury in Diabetic Nephropathy

Zhou

Yang

Lin

et al. 2022

BioMed Research International

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Diabetic nephropathy is a leading cause of end-stage renal disease in both developed and developing countries. It is lack of specific diagnosis, and the pathogenesis remains unclarified in diabetic nephropathy, following the unsatisfactory effects of existing treatments. Therefore, it is very meaningful to find biomarkers with high specificity and potential targets. Two datasets, GSE30529 and GSE47184 from GEO based on diabetic nephropathy tubular samples, were downloaded and merged after batch effect removal. A total of 545 different expression genes screened with log 2 FC > 0.5 were weighted gene coexpression correlation network analysis, and green module and blue module were identified. The results of KEGG analyses both in green module and GSEA analysis showed the same two enriched pathway, focal adhesion and viral myocarditis. Based on the intersection among WGCNA focal adhesion/Viral myocarditis, GSEA focal adhesion/viral myocarditis, and PPI network, 17 core genes, ACTN1, CAV1, PRKCB, PDGFRA, COL1A2, COL6A3, RHOA, VWF, FN1, HLA-F, HLA-DPB1, ITGB2, HLA-DRA, HLA-DMA, HLA-DPA1, HLA-B, and HLA-DMB, were identified as potential biomarkers in diabetic tubulointerstitial injury and were further validated externally for expression at GSE99325 and GSE104954 and clinical feature at nephroseq V5 online platform. CMap analysis suggested that two compounds, LY-294002 and bufexamac, may be new insights for therapeutics of diabetic tubulointerstitial injury. Conclusively, it was raised that a series of core genes may be as potential biomarkers for diagnosis and two prospective compounds.

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HDAC6‐mediated α‐tubulin deacetylation suppresses autophagy and enhances motility of podocytes in diabetic nephropathy

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 18 publications

References 50 publications

Autophagic LC3 ⁺ calcified extracellular vesicles initiate cartilage calcification in osteoarthritis

Autophagic LC3 ⁺ calcified extracellular vesicles initiate cartilage calcification in osteoarthritis

The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

Integrated Analysis of Multiple Microarray Studies to Identify Core Gene-Expression Signatures Involved in Tubulointerstitial Injury in Diabetic Nephropathy

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HDAC6‐mediated α‐tubulin deacetylation suppresses autophagy and enhances motility of podocytes in diabetic nephropathy

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 18 publications

References 50 publications

Autophagic LC3 + calcified extracellular vesicles initiate cartilage calcification in osteoarthritis

Autophagic LC3 + calcified extracellular vesicles initiate cartilage calcification in osteoarthritis

The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

Integrated Analysis of Multiple Microarray Studies to Identify Core Gene-Expression Signatures Involved in Tubulointerstitial Injury in Diabetic Nephropathy

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Autophagic LC3 ⁺ calcified extracellular vesicles initiate cartilage calcification in osteoarthritis

Autophagic LC3 ⁺ calcified extracellular vesicles initiate cartilage calcification in osteoarthritis