Structure and function of p62/SQSTM1 in the emerging framework of phase separation

Berkamp, Sabrina; Mostafavi, Siavash; Sachse, Carsten

doi:10.1111/febs.15672

Cited by 43 publications

(41 citation statements)

References 99 publications

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“…Please see in the text for details. Abbreviations: Ac: acetylation, dAc: de-acetylation, C: Cys, D: Asp, K: Lys, KIR: Keap1-interacting region, LIR: LC3-interacting region, NES: nuclear export signal/sequence, NLS: nuclear localization signal/sequence, PB1: Phox and Bem1p, S: Ser, T: Thr, TB: TRAF6-binding domain, UBA: ubiquitin-associated, ZZ: Zinc finger, [1,[12][13][14].…”

Section: Figurementioning

confidence: 99%

“…This increases p62-dependent selective autophagy as well as the assembly of p62 bodies, cytoplasmic aggregates containing ubiquitinated proteins and p62 [52]. Other publications suggest that p62 forms structures with more dynamic liquid-like properties, termed liquid droplets, which allow an exchange of their components with their environment [13,53]. This phase separation is mediated by the UBA and PB1 domains [1,12].…”

Section: P62 Is a Posttranslationally Modified Multi-domain Proteinmentioning

confidence: 99%

“…A subsequent phosphorylation at Ser403 by ULK1, CK2 (casein kinase 2), or TBK1 (TANK-binding kinase 1) enhances the affinity of the UBA domain for ubiquitin [73][74][75]. Upon binding of ubiquitin-conjugated substrates the complex can undergo phase separation by forming a dynamic liquid-like structure [13]. The LIR domain of p62 interacts with LC3 present on autophagosomes (Figure 2).…”

Section: P62 Is a Cargo Receptor For Autophagymentioning

confidence: 99%

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The Pathways Underlying the Multiple Roles of p62 in Inflammation and Cancer

et al. 2021

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p62 is a highly conserved, multi-domain, and multi-functional adaptor protein critically involved in several important cellular processes. Via its pronounced domain architecture, p62 binds to numerous interaction partners, thereby influencing key pathways that regulate tissue homeostasis, inflammation, and several common diseases including cancer. Via binding of ubiquitin chains, p62 acts in an anti-inflammatory manner as an adaptor for the auto-, xeno-, and mitophagy-dependent degradation of proteins, pathogens, and mitochondria. Furthermore, p62 is a negative regulator of inflammasome complexes. The transcription factor Nrf2 regulates expression of a bundle of ROS detoxifying genes. p62 activates Nrf2 by interaction with and autophagosomal degradation of the Nrf2 inhibitor Keap1. Moreover, p62 activates mTOR, the central kinase of the mTORC1 sensor complex that controls cell proliferation and differentiation. Through different mechanisms, p62 acts as a positive regulator of the transcription factor NF-κB, a central player in inflammation and cancer development. Therefore, p62 represents not only a cargo receptor for autophagy, but also a central signaling hub, linking several important pro- and anti-inflammatory pathways. This review aims to summarize knowledge about the molecular mechanisms underlying the roles of p62 in health and disease. In particular, different types of tumors are characterized by deregulated levels of p62. The elucidation of how p62 contributes to inflammation and cancer progression at the molecular level might promote the development of novel therapeutic strategies.

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Section: Figurementioning

confidence: 99%

Section: P62 Is a Posttranslationally Modified Multi-domain Proteinmentioning

confidence: 99%

Section: P62 Is a Cargo Receptor For Autophagymentioning

confidence: 99%

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The Pathways Underlying the Multiple Roles of p62 in Inflammation and Cancer

et al. 2021

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“…The p62 protein, which is also known as sequestosome 1 (SQSTM1), is a selective autophagy connector protein that serves as a bridge between autophagy-related LC3 proteins and polyubiquitinated proteins. It then transports damaged proteins, mitochondria, and invading bacteria to autophagosomes for degradation ( 32 ). It has been determined that p62 can be used as a cargo receptor required for circadian clock autophagy and that it participates in autophagic degradation of ubiquitinated substrates.…”

Section: Connecting the Links Between Ferroptosis And Autophagymentioning

confidence: 99%

The Role of Ferroptosis in Cardiovascular Disease and Its Therapeutic Significance

Chen

Yan

et al. 2021

Front. Cardiovasc. Med.

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Cardiovascular diseases (CVDs) are the leading cause of deaths worldwide with regulated cell death playing an important role in cardiac pathophysiology. However, the classical mode of cell death cannot fully explain the occurrence and development of heart disease. In recent years, much research has been performed on ferroptosis, a new type of cell death that causes cell damage and contributes to the development of atherosclerosis, myocardial infarction, heart failure, and other diseases. In this review, we discuss the role of different organelles in ferroptosis and also focus on the relationship between autophagy and ferroptosis. Additionally, we describe the specific mechanism by which ferroptosis contributes to the development of CVD. Finally, we summarize the current research on ferroptosis-related pathway inhibitors and the applications of clinically beneficial cardiovascular drugs.

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“…However, a common mechanism how each mutation recognized throughout the gene encoding p62 protein causes ALS and FTD remains unclear. p62, initially identified as a 62 kDa protein, has multiple functional domains which include an N-terminal Phox1 and Bem1p (PB1) domain, a zinc finger (ZZ), a tumor necrosis factor receptor-associated factor 6 (TRAF6) binding (TB) motif, an LC3-interacting region (LIR), a Keap1-interacting region (KIR) and a ubiquitin-associated (UBA) domain (6,7). The protein localization is not limited to the cytoplasm, but can also be observed in the nucleus, in autophagosomes and on lysosomes (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Droplets of amyotrophic lateral sclerosis-associated p62/SQSTM1 mutants show slower inner fluidity

Omar

Ichimura

Kageyama

et al. 2021

Preprint

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A series of amyotrophic lateral sclerosis (ALS)-related proteins such as FUS, TDP-43 and hnRNPA1 has an ability to be liquid-liquid phase separation, and their disease-related mutations cause the transition of their responsible liquid droplets to aggregates. Missense mutations in SQSTM1/p62, which have been identified throughout the gene, are associated with ALS, frontotemporal degeneration (FTD) and Pagets disease of bone. SQSTM1/p62 protein forms liquid-droplets through the interaction with ubiquitinated proteins, and the droplet serves as a platform of autophagosome formation and anti-oxidative stress response via the LC3-interacting region (LIR) and Keap1-interacting region (KIR), respectively. However, it remains unclear whether ALS/FTD-related p62 mutations in LIR and KIR form aberrant liquid droplets, cause defective autophagy and stress response or both. To evaluate the effects of ALS/FTD-related p62 mutations in LIR and KIR on a major oxidative stress system, the Keap1-Nrf2 pathway and the autophagic turnover, we developed systems that enable to monitor them with high sensitivity. These systems revealed that some mutants but not all have their less abilities on the Nrf2-activation and show the delayed turnover. By contrast, while the sufficient ability to form liquid droplets, all droplets consisting of p62 mutants showed slower inner fluidity. These results indicate that like other ALS-related mutant proteins, a primary defect in ALS/FTD with p62 missense mutations is a qualitative change of p62-liquid droplets.

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Structure and function of p62/SQSTM1 in the emerging framework of phase separation

Cited by 43 publications

References 99 publications

The Pathways Underlying the Multiple Roles of p62 in Inflammation and Cancer

The Pathways Underlying the Multiple Roles of p62 in Inflammation and Cancer

The Role of Ferroptosis in Cardiovascular Disease and Its Therapeutic Significance

Droplets of amyotrophic lateral sclerosis-associated p62/SQSTM1 mutants show slower inner fluidity

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