When p62/Sequestosome‐1 binds to a ubiquitinated protein, it undergoes liquid–liquid phase separation (LLPS) and forms a membraneless organelle, p62 body. There are two major physiological functions ...of the p62 body. One is effective autophagic degradation of ubiquitinated proteins and the other is antioxidant stress response, both of which contribute to cellular homeostasis. In this review, I review the history of p62 research in relation to autophagy and outline the formation, degradation, and physiological functions of the p62 body.
The concept of macroautophagy was established in 1963, soon after the discovery of lysosomes in rat liver. Over the 50 years since, studies of liver autophagy have produced many important findings. ...The liver is rich in lysosomes and possesses high levels of metabolic-stress-induced autophagy, which is precisely regulated by concentrations of hormones and amino acids. Liver autophagy provides starved cells with amino acids, glucose and free fatty acids for use in energy production and synthesis of new macromolecules, and also controls the quality and quantity of organelles such as mitochondria. Although the efforts of early investigators contributed markedly to our current knowledge of autophagy, the identification of autophagy-related genes represented a revolutionary breakthrough in our understanding of the physiological roles of autophagy in the liver. A growing body of evidence has shown that liver autophagy contributes to basic hepatic functions, including glycogenolysis, gluconeogenesis and β-oxidation, through selective turnover of specific cargos controlled by a series of transcription factors. In this Review, we outline the history of liver autophagy study, and then describe the roles of autophagy in hepatic metabolism under healthy and disease conditions, including the involvement of autophagy in α1-antitrypsin deficiency, NAFLD, hepatocellular carcinoma and viral hepatitis.
p62/SQSTM1 is a stress‐inducible cellular protein that is conserved among metazoans but not in plants and fungi. p62/SQSTM1 has multiple domains that mediate its interactions with various binding ...partners and it serves as a signaling hub for diverse cellular events such as amino acid sensing and the oxidative stress response. In addition, p62/SQSTM1 functions as a selective autophagy receptor for degradation of ubiqutinated substrates. In the present review, we describe the current knowledge about p62 with regard to mammalian target of rapamycin complex 1 activation, the Keap1–Nrf2 pathway and selective autophagy.
SQSTM1 (also known as p62) is a multifunctional stress-inducible scaffold protein involved in diverse cellular processes. Its functions are tightly regulated through an extensive pattern of ...post-translational modifications, and include the isolation of cargos degraded by autophagy, induction of the antioxidant response by the Keap1-Nrf2 system, as well as the regulation of endosomal trafficking, apoptosis and inflammation. Accordingly, malfunction of SQSTM1 is associated with a wide range of diseases, including bone and muscle disorders, neurodegenerative and metabolic diseases, and multiple forms of cancer. In this Review, we summarize current knowledge regarding regulation, post-translational modifications and functions of SQSTM1, as well as how they are dysregulated in various pathogenic contexts.
Autophagy is a highly conserved bulk protein degradation pathway responsible for the turnover of long-lived proteins, disposal of damaged organelles, and clearance of aggregate-prone proteins. Thus, ...inactivation of autophagy results in cytoplasmic protein inclusions, which are composed of misfolded proteins and excess accumulation of deformed organelles, leading to liver injury, diabetes, myopathy, and neurodegeneration. Although autophagy has been considered non-selective, growing lines of evidence indicate the selectivity of autophagy in sorting vacuolar enzymes and in the removal of aggregate-prone proteins, unwanted organelles and microbes. Such selectivity by autophagy enables diverse cellular regulations, similar to the ubiquitin–proteasome pathway. In this review, we introduce the selective turnover of the ubiquitin- and LC3-binding protein ‘p62’ through autophagy and discuss its physiological significance.
p62 is a ubiquitously expressed cellular protein conserved in metazoa but not in plants and fungi, and is known as one of the selective substrates for autophagy. This protein is localized at the ...autophagosome formation site and directly interacts with LC3, an autophagosome-localizing protein, and it is incorporated subsequently into the autophagosome and finally degraded. Impaired autophagy is accompanied by the accumulation of p62, followed by the formation of aggregates positive for p62 and ubiquitinated proteins because of the nature of both self-oligomerization and the ubiquitin-binding capacity of p62. The p62-positive aggregates observed in hepatocytes of liver-specific Atg7-deficient mice are completely dispersed by additional loss of p62, suggesting the involvement of p62 in the formation of disease-related inclusion bodies. Importantly, similar aggregates known as Mallory bodies and intracellular hyaline bodies have been identified in hepatocellular carcinoma (HCC). However, the pathophysiological significance of such aggregates remains unclear. Recently, we identified the role of p62-positive aggregates in human HCC and autophagy-deficient tumors in tumor development through persistent activation of Nrf2, a transcription factor responsible for stress response.
p62 is a stress‐inducible protein able to change among binding partners, cellular localizations and form liquid droplet structures in a context‐dependent manner. This protein is mainly defined as a ...cargo receptor for selective autophagy, a process that allows the degradation of detrimental and unnecessary components through the lysosome. Besides this role, its ability to interact with multiple binding partners allows p62 to act as a main regulator of the activation of the Nrf2, mTORC1, and NF‐κB signaling pathways, linking p62 to the oxidative defense system, nutrient sensing, and inflammation, respectively. In the present review, we will present the molecular mechanisms behind the control p62 exerts over these pathways, their interconnection and how their deregulation contributes to cancer progression.
p62/SQSTM1 interacts with key regulator proteins for diverse signal transduction pathways including mTORC1 activation, NF‐κB signaling, the Keap1‐Nrf2 system, and selective autophagy and serves as a signaling hub for anabolism, inflammatory response, antioxidant response, and catabolism. In this State‐of‐the‐Art Review, we discuss about diverse roles of p62/SQSTM1 and about their deregulation in cancer.
Autophagy and the Keap1-Nrf2 system are major cellular defense mechanisms against metabolic and oxidative stress. These two systems are linked
phosphorylation of the ubiquitin binding autophagy ...receptor protein p62/SQSTM1 in the p62-Keap1-Nrf2 pathway. The p62-Keap1-Nrf2 pathway plays a protective role in normal cells; however, recent studies indicate that this pathway induces tumorigenesis of pre-malignant cells, and promotes the growth and drug resistance of tumor cells
metabolic reprogramming mediated by Nrf2 activation. These findings suggest that impairment of autophagy is involved in the acquisition of malignancy and maintenance of tumors, and furthermore, that p62/SQSTM1 could be a potential target for chemotherapy in cancers that harbor excess p62.
Selective autophagy Faruk, Mohammad Omar; Ichimura, Yoshinobu; Komatsu, Masaaki
Cancer science,
October 2021, Letnik:
112, Številka:
10
Journal Article
Recenzirano
Odprti dostop
While starvation‐induced autophagy is thought to randomly degrade cellular components, under certain circumstances autophagy selectively recognizes, sequesters, and degrades specific targets via ...autophagosomes. This process is called selective autophagy, and it contributes to cellular homeostasis by degrading specific soluble proteins, supramolecular complexes, liquid‐liquid phase‐separated droplets, abnormal or excess organelles, and pathogenic invasive bacteria. This means that autophagy, like the ubiquitin‐proteasome system, strictly regulates diverse cellular functions through its selectivity. In this short review, we focus on the mechanism of "selective" autophagy, which is rapidly being elucidated.
In this short review, we focus on the mechanism of "selective" autophagy, which is rapidly being elucidated.
Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to ...metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in β-oxidation following suppression of transactivation by PPARα. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPARα to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPARα activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPARα activation upon fasting by promoting degradation of NCoR1 and thus regulates β-oxidation and ketone bodies production.
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