The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1

Komatsu, Masaaki; Kurokawa, H.; Waguri, Satoshi; Taguchi, Keiko; Kobayashi, Akira; Ichimura, Yoshinobu; Sou, Yu‐shin; Ueno, Izumi; Sakamoto, Ayako; Tong, Kit I.; Kim, Mi-Hee; Nishito, Yasumasa; Iemura, Shun Ichiro; Natsume, Tohru; Ueno, Takashi; Kominami, Eiki; Motohashi, Hozumi; Tanaka, Keiji; Yamamoto, Masayuki

doi:10.1038/ncb2021

Cited by 2,069 publications

(1,968 citation statements)

References 53 publications

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“…Finally, p62/SQSTM1 binds to Kelch-like ECHassociated protein 1 (Keap1) through a Keap1 interacting region (KIR) (aa 346-355) (Jain et al 2010;Komatsu et al 2010;Lau et al 2010). The KIR binds to Keap1 on a site essential for Keap1 to interact with and repress nuclear factor erythroid 2-like 2 (NFE2L2)'s activation, albeit with much lower affinity (Komatsu et al 2010).…”

Section: Structurementioning

confidence: 99%

“…The KIR binds to Keap1 on a site essential for Keap1 to interact with and repress nuclear factor erythroid 2-like 2 (NFE2L2)'s activation, albeit with much lower affinity (Komatsu et al 2010). Nevertheless, p62/SQSTM1 can activate NFE2L2 by sequestering Keap1 into p62 bodies when its levels are increased, either due to autophagy impairment or direct p62/SQSTM1 overexpression (Jain et al 2010;Komatsu et al 2010). Interestingly, p62/SQSTM1 ability to bind Keap1 seems to be dependent on its ability to form oligomers through the PB1 domain (Jain et al 2010).…”

Section: Structurementioning

confidence: 99%

“…NFE2L2 can also be activated by p62/SQSTM1 in conditions where oxidative stress is not present: p62/ SQSTM1 binds to Keap1 with the KIR on the same sequence that binds to the ETGE domain of NFE2L2 (Jain et al 2010;Komatsu et al 2010;Lau et al 2010;Copple et al 2010). The KIR has a much weaker affinity for Keap1 than NFE2L2 (Komatsu et al 2010), hence it has been proposed that p62/SQSTM1 can activate the NFE2L2 pathway only in pathological conditions, for example, when autophagy is impaired.…”

Section: Antioxidant Responsementioning

confidence: 99%

“…The KIR has a much weaker affinity for Keap1 than NFE2L2 (Komatsu et al 2010), hence it has been proposed that p62/SQSTM1 can activate the NFE2L2 pathway only in pathological conditions, for example, when autophagy is impaired. Nevertheless, a fraction of Keap1 associates constitutively with p62/ SQSMT1 (Copple et al 2010).…”

Section: Antioxidant Responsementioning

confidence: 99%

“…p62/SQSTM1 brings Keap1 into sequestosomes, effectively impairing its ability to bind NFE2L2 (Lau et al 2010), and Keap1 presence into sequestosomes seems to facilitate their clearance through autophagy (Fan et al 2010), which would further reduce Keap1 levels and its ability to bind NFE2L2. p62/SQSTM1 relevance in aging and age-related pathologies p62/SQSTM1 is involved in a variety of cellular processes that are relevant for aging, including protein degradation (Pankiv et al 2007;Seibenhener et al 2004), mitophagy (Narendra et al 2010a;Geisler et al 2010a;Tang et al 2011), oxidative stress response (Jain et al 2010;Komatsu et al 2010;Lau et al 2010), metabolism regulation (Moscat and Diaz-Meco 2011), and inflammation (Lee et al 2012). The role of p62/ SQSTM1 in aging and age-related diseases is not fully understood yet, although experimental evidence suggests it is likely a critical factor: expression of p62/ SQSTM1 declines with age in mice (Kwon et al 2012), loss of p62/SQSTM1 reduces lifespan and shows several age-related effects in animal models, and reduced p62/SQSTM1 correlates with age-related pathologies in human tissues.…”

Section: Antioxidant Responsementioning

confidence: 99%

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p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

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124

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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Section: Structurementioning

confidence: 99%

Section: Structurementioning

confidence: 99%

Section: Antioxidant Responsementioning

confidence: 99%

Section: Antioxidant Responsementioning

confidence: 99%

Section: Antioxidant Responsementioning

confidence: 99%

See 3 more Smart Citations

p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

AGE

124

View full text Add to dashboard Cite

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p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

et al. 2016

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p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies. Chronic p62 elevation contributes to HCC development by preventing oncogene-induced senescence and death of cancer-initiating cells and enhancing their proliferation. In this review, we discuss p62-mediated signaling pathways and their roles in liver pathophysiology, especially NASH and HCC.

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Endothelial cell autophagy in homeostasis and cancer

et al. 2021

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Autophagy, the major lysosomal pathway for the degradation and recycling of cytoplasmic materials, is increasingly recognized as a major player in endothelial cell (EC) biology and vascular pathology. Particularly in solid tumors, tumor microenvironmental stress such as hypoxia, nutrient deprivation, inflammatory mediators, and metabolic aberrations stimulates autophagy in tumor‐associated blood vessels. Increased autophagy in ECs may serve as a mechanism to alleviate stress and restrict exacerbated inflammatory responses. However, increased autophagy in tumor‐associated ECs can re‐model metabolic pathways and affect the trafficking and surface availability of key mediators and regulators of the interplay between EC and immune cells. In line with this, heightened EC autophagy is involved in pathological angiogenesis, inflammatory, and immune responses. Here, we review major cellular and molecular mechanisms regulated by autophagy in ECs under physiological conditions and discuss recent evidence implicating EC autophagy in tumor angiogenesis and immunosurveillance.

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The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1

Cited by 2,069 publications

References 53 publications

p62/SQSTM1 at the interface of aging, autophagy, and disease

p62/SQSTM1 at the interface of aging, autophagy, and disease

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

Endothelial cell autophagy in homeostasis and cancer

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