p62/<scp>SQSTM</scp>1 functions as a signaling hub and an autophagy adaptor

Katsuragi, Yoshihisa; Ichimura, Yoshinobu; Komatsu, Masaaki

doi:10.1111/febs.13540

Cited by 654 publications

(577 citation statements)

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“…Abnormally folded proteins can aggregate and form inclusion bodies in the cell, thereby perturbing intracellular signaling and cell activity. Although these aggregates can be eliminated by p62-mediated ALS (25,26), the accumulation of p62-containing aggregates indicates an impairment of the ALS in embryonic cells of diabetic mice. Three proteins associated with neurodegenerative diseases, α-Syn, Parkin, and Htt, also form aggregates in the embryos of diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

“…Aggregates of ubiquitinylated proteins are subject to ALS clearance, mediated by ubiquitin-binding protein p62 (25,26). Doublelabeling with Proteostat to detect protein aggregates and an antibody to detect p62 revealed colocalization of protein aggregates and p62 ( Fig.…”

Section: Significancementioning

confidence: 94%

“…Protein aggregates can be eliminated by the autophagic-lysosomal system (ALS) (23,24). The transfer of ubiquitinylated proteins to the ALS is mediated by a ubiquitin-binding protein, p62, also known as Sequestosome-1 (25,26). Protein aggregates containing p62 are commonly seen in neurodegenerative diseases, indicating deficiency of the ALS in the pathogenesis of these diseases (27).…”

mentioning

confidence: 99%

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Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

Zhao

Cao

Reece

2017

Proc. Natl. Acad. Sci. U.S.A.

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Diabetes mellitus in early pregnancy increases the risk in infants of birth defects, such as neural tube defects (NTDs), known as diabetic embryopathy. NTDs are associated with hyperglycemia-induced protein misfolding and Caspase-8–induced programmed cell death. The present study shows that misfolded proteins are ubiquitinylated, suggesting that ubiquitin-proteasomal degradation is impaired. Misfolded proteins form aggregates containing ubiquitin-binding protein p62, suggesting that autophagic-lysosomal clearance is insufficient. Additionally, these aggregates contain the neurodegenerative disease-associated proteins α-Synuclein, Parkin, and Huntingtin (Htt). Aggregation of Htt may lead to formation of a death-inducing signaling complex of Hip1, Hippi, and Caspase-8. Treatment with chemical chaperones, such as sodium 4-phenylbutyrate (PBA), reduces protein aggregation in neural stem cells in vitro and in embryos in vivo. Furthermore, treatment with PBA in vivo decreases NTD rate in the embryos of diabetic mice, as well as Caspase-8 activation and cell death. Enhancing protein folding could be a potential interventional approach to preventing embryonic malformations in diabetic pregnancies.

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 94%

mentioning

confidence: 99%

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Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

Zhao

Cao

Reece

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…17,[20][21][22] The SQSTM1 (sequestosome 1, p62) protein is a ubiquitin-binding scaffold molecule that plays a key role in autophagic degradation of ubiquitinated proteins, [23][24][25][26][27][28][29] and the degradation of SQSTM1 with tumor-related antigen may promote T-cell-mediated immunity. [30][31][32] Colorectal cancer represents a heterogeneous group of neoplasms resulting from genomic and epigenomic alterations, which influence and are influenced by tumor-host interactions.…”

Section: Introductionmentioning

confidence: 99%

Tumor SQSTM1 (p62) expression and T cells in colorectal cancer

et al. 2017

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Evidence suggests that activation of autophagy in neoplastic cells potentiates antitumor immunity through cross-presentation of tumor-associated antigens to T cells and release of immune mediators. The SQSTM1 (sequestosome 1, p62) protein is degraded by activated autophagy, and might enhance immune response to tumor cells. We hypothesized that tumor SQSTM1 expression level might be inversely associated with T-cell densities in colorectal carcinoma tissue. We evaluated tumor SQSTM1 expression by immunohistochemistry in 601 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study. Ordinal logistic regression analyses were conducted to assess the association of tumor SQSTM1 expression with CD3, or FOXP3 C cell density in tumor tissue, controlling for potential confounders, including tumor status of microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation level, and KRAS, BRAF, and PIK3CA mutations. Tumor SQSTM1 expression level was inversely associated with FOXP3 C cell density (p trend D 0.006), but not with CD3C , CD8 C , or CD45RO C cell density (with the adjusted a level of 0.01 for multiple hypothesis testing). For a unit increase in quartile categories of FOXP3 C cell density, multivariable odds ratios were 0.66 [95% confidence interval (CI), 0.45-0.98] for intermediate-level SQSTM1 expression, and 0.55 (95% CI, 0.36-0.83) for high-level SQSTM1 expression, compared with low-level SQSTM1 expression. Tumor SQSTM1 expression is inversely associated with FOXP3 C cell density in colorectal cancer tissue, suggesting a possible role of SQSTM1-expressing carcinoma cells on regulatory T cells in the tumor microenvironment.Abbreviations: ATP, adenosine triphosphate; CI, confidence interval; CIMP, CpG island methylator phenotype; FFPE, formalin-fixed paraffin-embedded; LINE-1, long interspersed nucleotide element-1; MSI, microsatellite instability;

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“…Therefore, elucidating the molecular mechanisms underlying pancreatic β-cell dysfunction is a key to understanding the pathology of diabetes [3,4]. Sequestosome 1 (SQSTM1, referred to hereafter as p62) is a multifunctional scaffold protein that can interact with several signaling pathways through its functional subdomains, including the Phox and Bem1 (PB1) domain, zinc-finger domain, TNF receptor-associated factor 6 (TRAF6)-binding domain, and Kelch-like ECHassociated protein 1 (Keap1) interacting region (KIR) [5][6][7]. p62/SQSTM1 can activate the antioxidant response by interacting with the Keap1-Nrf2 pathway [8][9][10].…”

mentioning

confidence: 99%

Normal pancreatic β-cell function in mice with <i>RIP-Cre</i>-mediated inactivation of p62/SQSTM1

et al. 2018

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Abstract. Recent studies have suggested that decreased pancreatic β-cell function and mass are common features of patients with type 2 diabetes mellitus. Pancreatic β-cell homeostasis is regulated by various types of signaling molecules and stress responses. Sequestosome 1/p62 (SQSTM1, hereafter referred to as p62) is a ubiquitin-binding adaptor protein involved in cell signaling, oxidative stress, and autophagy. Because p62 appears to play an important role in maintaining mitochondrial quality control, it is possible that the loss of p62 in pancreatic β cells contributes to mitochondrial dysfunction, and thus leading to impaired glucose tolerance. In this study we investigated the physiological roles of p62 by inactivating p62 in a β-cell specific manner. We found that firstly, rat insulin-2 promoter-Cre (RIP-Cre)-mediated p62 inactivation did not cause body weight gain, although ubiquitous inactivation of p62 was previously shown to result in severe obesity. Secondly, we found no gross structural disorganization of the islets of p62-deficient mice. Consistent with normal islet morphology, no impairment in glucose tolerance was observed in mice with RIP-Cre-mediated p62 deletion. These results suggest that p62 is dispensable for normal islet organization and β-cell function.Key words: Islets, β cell, Diabetes, p62, Sequestosome 1 TYPE 2 DIABETES MELLITUS is a metabolic disorder characterized by hyperglycemia resulting from the complex interplay of multiple genetic and environmental factors, resulting in both decreased insulin action on target tissues and defective pancreatic β-cell insulin secretion in response to glucose [1]. The natural history of diabetes is strongly associated with the disability of pan-

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p62/SQSTM1 functions as a signaling hub and an autophagy adaptor

Cited by 654 publications

References 46 publications

Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

Tumor SQSTM1 (p62) expression and T cells in colorectal cancer

Normal pancreatic β-cell function in mice with <i>RIP-Cre</i>-mediated inactivation of p62/SQSTM1

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