p62 filaments capture and present ubiquitinated cargos for autophagy

Zaffagnini, Gabriele; Savova, Adriana; Danieli, Alberto; Romanov, Julia; Tremel, Shirley; Ebner, Michael; Peterbauer, Thomas; Sztacho, Martin; Trapannone, Riccardo; Tarafder, Abul K.; Sachse, Carsten; Martens, Sascha

doi:10.15252/embj.201798308

Cited by 272 publications

(399 citation statements)

References 74 publications

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“…In agreement with previous in vitro observations [23], NBR1 facilitated the formation of p62-liquid bodies in cells (Fig 1). How does NBR1 promote phase separation of p62?…”

Section: Discussionsupporting

confidence: 93%

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NBR 1‐mediated p62‐liquid droplets enhance the Keap1‐Nrf2 system

et al. 2020

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p62/SQSTM1 is a multivalent protein that has the ability to cause liquid–liquid phase separation and serves as a receptor protein that participates in cargo isolation during selective autophagy. This protein is also involved in the non‐canonical activation of the Keap1‐Nrf2 system, a major oxidative stress response pathway. Here, we show a role of neighbor of BRCA1 gene 1 (NBR1), an autophagy receptor structurally similar to p62/SQSTM1, in p62‐liquid droplet formation and Keap1‐Nrf2 pathway activation. Overexpression of NBR1 blocks selective degradation of p62/SQSTM1 through autophagy and promotes the accumulation and phosphorylation of p62/SQSTM1 in liquid‐like bodies, which is required for the activation of Nrf2. NBR1 is induced in response to oxidative stress, which triggers p62‐mediated Nrf2 activation. Conversely, loss of Nbr1 suppresses not only the formation of p62/SQSTM1‐liquid droplets, but also of p62‐dependent Nrf2 activation during oxidative stress. Taken together, our results show that NBR1 mediates p62/SQSTM1‐liquid droplet formation to activate the Keap1‐Nrf2 pathway.

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“…In agreement with previous in vitro observations [23], NBR1 facilitated the formation of p62-liquid bodies in cells (Fig 1). How does NBR1 promote phase separation of p62?…”

Section: Discussionsupporting

confidence: 93%

“…NBR1 enhances the protein levels of p62 partially independent on Nrf2. is required for phase separation [6,23]. Thus, it is likely that the increase in the phosphorylation states of p62 produced by NBR1 positively influences the formation of p62 bodies.…”

Section: Discussionmentioning

confidence: 99%

NBR 1‐mediated p62‐liquid droplets enhance the Keap1‐Nrf2 system

et al. 2020

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“…2A). However, two recent publications showed that the structures formed by SQSTM1 undergo phase-separation and have liquid-like properties that depend on the presence of ubiquitin chains (Sun et al, 2018;Zaffagnini et al, 2018) (Fig. 2B).…”

Section: Box 1 Selective Autophagy Is Mediated By a Several Receptormentioning

confidence: 94%

p62/SQSTM1 – steering the cell through health and disease

Sánchez‐Martín

Komatsu

2018

Journal of Cell Science

226

179

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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.

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“…A recent report found that KEAP1/ CUL3 ubiquitylates p62 on its ubiquitin-associated domain (UBA) and that this interaction is crucial for the recruitment of p62 into the autophagosome (123,124). Furthermore, a role for p62 and polyubiquitin in the formation of phase-separated autophagic intermediates has been recently defined (125)(126)(127). Conformationally strained KEAP1 due to ANCHOR mutations may result in decreased or absent p62 ubiquitylation, preventing tethering to LC3 for autophagosome formation and maturation.…”

Section: Parentalmentioning

confidence: 99%

p62-Dependent Phase Separation of Patient-Derived KEAP1 Mutations and NRF2

Cloer

Siesser

Cousins

et al. 2018

Molecular and Cellular Biology

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Cancer-derived loss-of-function mutations in the KEAP1 tumor suppressor gene stabilize the NRF2 transcription factor, resulting in a pro-survival gene expression program that alters cellular metabolism and neutralizes oxidative stress. In a recent genotype-phenotype study, we classified 40% of KEAP1 mutations as ANCHOR mutants. By immunoprecipitation, these mutants bind more NRF2 than wild-type KEAP1 and ubiquitylate NRF2, but are incapable of promoting NRF2 degradation. BioID-based protein interaction studies confirmed increased abundance of NRF2 within the KEAP1 ANCHOR mutant complexes with no other statistically significant changes to the complexes. Discrete molecular dynamic simulation modeling and limited proteolysis suggest that the ANCHOR mutations stabilize residues in KEAP1 that contact NRF2. The modeling supports an intramolecular salt bridge between the R470C ANCHOR mutation and E493; mutation of the E493 residue confirmed the model, resulting in the ANCHOR phenotype. In live cells, the KEAP1 R320Q and R470C ANCHOR mutants co-localize with NRF2, p62/SQSTM1, and polyubiquitin in structured spherical droplets that rapidly fuse and dissolve. Transmission electron microscopy coupled with confocal fluorescent imaging revealed membraneless phase-separated biomolecular condensates. We present a model wherein ANCHOR mutations form p62-dependent biomolecular condensates that may represent a transitional state between impaired proteasomal degradation and autophagy.

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p62 filaments capture and present ubiquitinated cargos for autophagy

Cited by 272 publications

References 74 publications

NBR 1‐mediated p62‐liquid droplets enhance the Keap1‐Nrf2 system

NBR 1‐mediated p62‐liquid droplets enhance the Keap1‐Nrf2 system

p62/SQSTM1 – steering the cell through health and disease

p62-Dependent Phase Separation of Patient-Derived KEAP1 Mutations and NRF2

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