1.Advances in molecular function of p62 protein and its role in diseases.
Xinying SUI ; Ping XU ; Changzhu DUAN ; Yanchang LI
Chinese Journal of Biotechnology 2023;39(4):1374-1389
Sequestosome 1 (SQSTM1/p62) is a selective autophagy adaptor protein that plays an important role in the clearance of proteins to be degraded as well as in the maintenance of cellular proteostasis. p62 protein has multiple functional domains, which interact with several downstream proteins to precisely regulate multiple signaling pathways, thereby linking p62 to oxidative defense systems, inflammatory responses and nutrient sensing. Studies have shown that mutation or abnormal expression of p62 is closely related to the occurrence and development of various diseases, including neurodegenerative diseases, tumors, infectious diseases, genetic diseases and chronic diseases. This review summarizes the structural features and molecular functions of p62. Moreover, we systematically introduce its multiple functions in protein homeostasis and regulation of signaling pathways. Furthermore, the complexity and versatility of p62 in the occurrence and development of diseases are summarized, with the aim to provide a reference for understanding the function of p62 protein and facilitating related disease research.
Humans
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Autophagy/genetics*
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Sequestosome-1 Protein/metabolism*
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Adaptor Proteins, Signal Transducing/metabolism*
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Signal Transduction
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Neoplasms/genetics*
3.Regulation of FN1 degradation by the p62/SQSTM1-dependent autophagy-lysosome pathway in HNSCC.
Xinchen LIU ; Lin MENG ; Xing LI ; Daowei LI ; Qilin LIU ; Yumeng CHEN ; Xiangwei LI ; Wenhuan BU ; Hongchen SUN
International Journal of Oral Science 2020;12(1):34-34
Epithelial-mesenchymal transition (EMT) is involved in both physiological and pathological processes. EMT plays an essential role in the invasion, migration and metastasis of tumours. Autophagy has been shown to regulate EMT in a variety of cancers but not in head and neck squamous cell carcinoma (HNSCC). Herein, we investigated whether autophagy also regulates EMT in HNSCC. Analyses of clinical data from three public databases revealed that higher expression of fibronectin-1 (FN1) correlated with poorer prognosis and higher tumour pathological grade in HNSCC. Data from SCC-25 cells demonstrated that rapamycin and Earle's balanced salt solution (EBSS) promoted autophagy, leading to increased FN1 degradation, while 3-methyladenine (3-MA), bafilomycin A1 (Baf A1) and chloroquine (CQ) inhibited autophagy, leading to decreased FN1 degradation. On the other hand, autophagic flux was blocked in BECN1 mutant HNSCC Cal-27 cells, and rapamycin did not promote autophagy in Cal-27 cells; also in addition, FN1 degradation was inhibited. Further, we identified FN1 degradation through the lysosome-dependent degradation pathway using the proteasome inhibitor MG132. Data from immunoprecipitation assays also showed that p62/SQSTM1 participated as an autophagy adapter in the autophagy-lysosome pathway of FN1 degradation. Finally, data from immunoprecipitation assays demonstrated that the interaction between p62 and FN1 was abolished in p62 mutant MCF-7 and A2780 cell lines. These results indicate that autophagy significantly promotes the degradation of FN1. Collectively, our findings clearly suggest that FN1, as a marker of EMT, has adverse effects on HNSCC and elucidate the autophagy-lysosome degradation mechanism of FN1.
Autophagy
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Cell Line, Tumor
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Female
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Fibronectins
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Humans
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Lysosomes/metabolism*
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Ovarian Neoplasms
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Sequestosome-1 Protein/metabolism*
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Squamous Cell Carcinoma of Head and Neck
4.Mechanism of radiosensitization of 3-methyladenine in human hypopharynx cancer cells.
Zhi-ping TANG ; Yao-dong XU ; Jie-ren PENG ; Yong-kang OU ; Zhong GUAN
Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2012;47(11):937-941
OBJECTIVETo investigate the radiosensitizing effect and its mechanism of 3-MA in human hypopharynx cancer cells.
METHODS5 mmol/L of 3-MA combined with 2 Gy or 4 Gy of X-ray was utilized to deal with Fadu cells, and the cell livability (cloning efficiency) and DNA lesion severity (tail moment) of each groups was examined by clonogenic survival assay and comet assay, then differences were compared between groups by independent-sample T test. Fadu cells were then treated with different dose of 3-MA (1, 2, 5, 10 mmol/L), the alteration of cell cycle distribution was detected by flow cytometer, and differences among groups were analyzed through one-way analysis of variance. The expression of p62 and cyclinB1 in each group was examined by western blot.
RESULTSThe livability and DNA lesion severity of cells treated with 3-MA alone showed no notable variation. Compared with non-3-MA groups, the cloning efficiency of cells treated with 3-MA decreased much more after irradiated with 2 Gy or 4 Gy of X-ray (t = 13.41 or 13.98, P < 0.001), and the cells showed a more serious DNA lesion (t = 7.07 or 6.91, P < 0.001). The G2/M percentages of cells in the control group and groups treated with 1, 2, 5, 10 mmol/L of 3-MA were 17.10 ± 1.20, 23.30 ± 2.3, 39.90 ± 3.12, 58.47 ± 1.65, 76.13 ± 3.51 and differences among groups were statistically significant (F = 278.4, P < 0.05). The expression of p62 in cells treated with 3-MA showed a dose-dependent increase, while cyclinB1 showed a dose-dependent decrease.
CONCLUSIONSThe autophagy inhibitor 3-MA could enhance radiosensitivity of human hypopharynx cancer cells by inducing G2/M arrest and enhancing irradiation-induced DNA damage.
Adaptor Proteins, Signal Transducing ; metabolism ; Adenine ; analogs & derivatives ; pharmacology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cyclin B1 ; metabolism ; DNA Damage ; drug effects ; Humans ; Radiation Tolerance ; drug effects ; Radiation-Sensitizing Agents ; pharmacology ; Sequestosome-1 Protein
5.Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson's disease.
Pingping SONG ; Shanshan LI ; Hao WU ; Ruize GAO ; Guanhua RAO ; Dongmei WANG ; Ziheng CHEN ; Biao MA ; Hongxia WANG ; Nan SUI ; Haiteng DENG ; Zhuohua ZHANG ; Tieshan TANG ; Zheng TAN ; Zehan HAN ; Tieyuan LU ; Yushan ZHU ; Quan CHEN
Protein & Cell 2016;7(2):114-129
Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson's disease (PD), respectively, which manifested with the selective vulnerability of neuronal cells in substantia nigra (SN) and striatum (STR) regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.
Adaptor Proteins, Signal Transducing
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chemistry
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metabolism
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Animals
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HEK293 Cells
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Heat-Shock Proteins
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chemistry
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metabolism
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Humans
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Lysine
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metabolism
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Mice
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Neurons
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metabolism
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pathology
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Oxidopamine
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pharmacology
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Parkinson Disease
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metabolism
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pathology
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Proteasome Endopeptidase Complex
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metabolism
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Protein Stability
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Proteolysis
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drug effects
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Sequestosome-1 Protein
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Ubiquitin-Protein Ligases
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metabolism
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Ubiquitination
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drug effects
6.Sirt1 regulates testosterone biosynthesis in Leydig cells via modulating autophagy.
Muhammad Babar KHAWAR ; Chao LIU ; Fengyi GAO ; Hui GAO ; Wenwen LIU ; Tingting HAN ; Lina WANG ; Guoping LI ; Hui JIANG ; Wei LI
Protein & Cell 2021;12(1):67-75
Animals
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Autophagy/genetics*
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Cholesterol/metabolism*
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Gene Expression Regulation
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Integrases/metabolism*
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Leydig Cells/metabolism*
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Male
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Mice, Knockout
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Multienzyme Complexes/metabolism*
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Phosphoproteins/metabolism*
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Primary Cell Culture
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Progesterone Reductase/metabolism*
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RNA Splicing Factors/metabolism*
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Scavenger Receptors, Class B/metabolism*
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Sequestosome-1 Protein/metabolism*
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Signal Transduction
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Sirtuin 1/genetics*
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Sodium-Hydrogen Exchangers/metabolism*
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Steroid 17-alpha-Hydroxylase/metabolism*
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Steroid Isomerases/metabolism*
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Testosterone/genetics*