Proteolysis articles within Nature

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  • Article
    | Open Access

    The E3 ligase SIFI is identified as a dedicated silencing factor of the integrated stress response, a finding that has implications for the development of therapeutics for neurodegenerative diseases caused by mitochondrial protein import stress.

    • Diane L. Haakonsen
    • , Michael Heider
    •  & Michael Rapé

  • Article |

    A technique to detect the release of N-terminal fragments of Drosophila adhesion G-protein-coupled receptors (aGPCRs) provides insight into the dissociation of aGPCRs, and shows that receptor autoproteolysis enables non-cell-autonomous activity of aGPCRs in the brain.

    • Nicole Scholz
    • , Anne-Kristin Dahse
    •  & Tobias Langenhan

  • Article
    | Open Access

    Cryo-electron microscopy structures of Staphylococcus aureus BlaR1 reveal dynamic signalling states regulating broad spectrum β-lactam antibiotic resistance through cleavage of the transcriptional repressor BlaI and induced expression of the β-lactamase blaZ and the β-lactam-resistant cell-wall transpeptidase mecA.

    • J. Andrew N. Alexander
    • , Liam J. Worrall
    •  & Natalie C. J. Strynadka

  • Article
    | Open Access

    A small-molecule inhibitor of TMPRSS2 is effective against SARS-CoV-2 variants of concern in human lung cells and in donor-derived colonoids, and also shows prophylactic and therapeutic benefits in a mouse model of COVID-19.

    • Tirosh Shapira
    • , I. Abrrey Monreal
    •  & François Jean

  • Article |

    Structures of Ubr1 in complex with Ubc2, ubiquitin and two N-degron peptides reveal a Ubc2-binding region and an acceptor ubiquitin-binding loop on Ubr1, providing mechanistic insights into the initiation and elongation steps of ubiquitination catalysed by Ubr1.

    • Man Pan
    • , Qingyun Zheng
    •  & Minglei Zhao

  • Article |

    Biochemical and genetics studies identify CRL4AMBRA1 as the ubiquitin ligase that has a key role in regulating the stability of D-type cyclins during cell-cycle progression.

    • Daniele Simoneschi
    • , Gergely Rona
    •  & Michele Pagano

  • Article |

    AMBRA1 is the main regulator of the degradation of D-type cyclins, and loss of AMBRA1 promotes cell proliferation and tumour growth, and reduces the sensitivity of cancer cells to inhibition of CDK4 and CDK6.

    • Andrea C. Chaikovsky
    • , Chuan Li
    •  & Julien Sage

  • Article |

    Binding of the small molecule BI-3802 to the oncogenic transcription factor B cell lymphoma 6 (BCL6) induces polymerization of BCL6, leading to its ubiquitination by SIAH1 and proteasomal degradation.

    • Mikołaj Słabicki
    • , Hojong Yoon
    •  & Benjamin L. Ebert

  • Article |

    Structural studies of the dimerization quality control E3 ubiquitin ligase SCF–FBXL17 indicate that its selectivity for aberrant complex formation is based on recognizing both shape and complementarity of interacting domains.

    • Elijah L. Mena
    • , Predrag Jevtić
    •  & Michael Rape

  • Article |

    Lysosome-targeting chimaeras—in which a small molecule or antibody is connected to a glycopeptide ligand to form a conjugate that can bind a cell-surface lysosome-shuttling receptor and a protein target—are used to achieve the targeted degradation of extracellular and membrane proteins.

    • Steven M. Banik
    • , Kayvon Pedram
    •  & Carolyn R. Bertozzi

  • Article |

    During nutrient stress, ribosomal protein abundance is regulated primarily by translational and non-autophagic degradative mechanisms, but ribosome density per cell is largely maintained by reductions in cell volume and rates of cell division.

    • Heeseon An
    • , Alban Ordureau
    •  & J. Wade Harper

  • Article |

    Hyperosmotic stress leads to a phase separation of the proteasome, triggered by interactions between RAD23B and ubiquitylated proteins, which bring together p97 and proteasome-associated proteins into nuclear proteolytic foci.

    • Sayaka Yasuda
    • , Hikaru Tsuchiya
    •  & Yasushi Saeki

  • Article |

    In Saccharomyces cerevisiae, Ubx2 promotes clearing trapped precursor proteins from the channel of the translocase of the outer membrane, in a translocation-associated degradation pathway that maintains the protein import capacity of mitochondria.

    • Christoph U. Mårtensson
    • , Chantal Priesnitz
    •  & Thomas Becker

  • Letter |

    Hypoxia in the shoot meristem of Arabidopsis links the regulation of metabolic activity to development by inhibiting proteolysis of a substrate of the N-degron pathway, which controls class-III homeodomain-leucine zipper transcription factors.

    • Daan A. Weits
    • , Alicja B. Kunkowska
    •  & Francesco Licausi

  • Article |

    Cryo-electron microscopy structures and dynamics of a substrate-engaged human 26S proteasome reveal in atomic detail three principal modes of coordinated ATP hydrolysis that regulate different steps in the degradation of a ubiquitylated protein.

    • Yuanchen Dong
    • , Shuwen Zhang
    •  & Youdong Mao

  • Article |

    Disulfiram is metabolized into copper–diethyldithiocarbamate, which binds to NPL4 and induces its aggregation in cells, leading to blockade of the p97–NPL4–UFD1 pathway and induction of a complex cellular phenotype that results in cell death.

    • Zdenek Skrott
    • , Martin Mistrik
    •  & Jiri Bartek

  • Letter |

    The polyglutamine domain in ataxin 3, which is expanded in spinocerebellar ataxia type 3, allows normal ataxin 3 to interact with and deubiquitinate beclin 1 and thereby to promote autophagy.

    • Avraham Ashkenazi
    • , Carla F. Bento
    •  & David C. Rubinsztein

  • Article |

    Proteasome abundance is crucial for cell survival, but how cells maintain adequate amounts of proteasome is unclear; an analysis in yeast identifies TORC1 and Mpk1 as central components of a pathway regulating proteasome homeostasis through the coordinated regulation of regulatory particle assembly chaperones and proteasome subunits—this pathway is evolutionarily conserved with mTOR and ERK5 regulating proteasome abundance in mammals.

    • Adrien Rousseau
    •  & Anne Bertolotti

  • Letter |

    The proteasome-associated enzyme USP14 regulates protein degradation by removing ubiquitin from proteins; here it is shown that USP14 removes ubiquitin chains from in vitro generated cyclin B conjugates en bloc and within milliseconds, before the proteasome has a chance to initiate degradation, and proceeds until a single chain remains.

    • Byung-Hoon Lee
    • , Ying Lu
    •  & Daniel Finley

  • Article |

    Lenalidomide, a derivative of thalidomide, is an effective drug for myelodysplastic syndrome; lenalidomide binds the CRL4CRBN E3 ubiquitin ligase and promotes degradation of casein kinase 1a, on which the malignant cells rely for survival.

    • Jan Krönke
    • , Emma C. Fink
    •  & Benjamin L. Ebert

  • Letter |

    A protein degradation pathway is found at the inner nuclear membrane that is distinct from, but complementary to, endoplasmic-reticulum-associated protein degradation, and which is mediated by the Asi protein complex; a genome-wide library screening of yeast identifies more than 20 substrates of this pathway, which is shown to target mislocalized integral membrane proteins for degradation.

    • Anton Khmelinskii
    • , Ewa Blaszczak
    •  & Michael Knop

  • Letter |

    Ubiquitin, known for its role in post-translational modification of other proteins, undergoes post-translational modification itself; after a decrease in mitochondrial membrane potential, the kinase enzyme PINK1 phosphorylates ubiquitin at Ser 65, and the phosphorylated ubiquitin then interacts with ubiquitin ligase (E3) enzyme parkin, which is also phosphorylated by PINK1, and this process is sufficient for full activation of parkin enzymatic activity.

    • Fumika Koyano
    • , Kei Okatsu
    •  & Noriyuki Matsuda

  • Letter |

    Human embryonic stem cells (hESCs) are shown to have high 26S/30S proteasome activity owing to increased expression of the 19S proteasome subunit PSMD11; FOXO4 regulates proteasome activity in hESCs by modulating PSMD11 expression, and the high proteasome activity decreases after induced differentiation.

    • David Vilchez
    • , Leah Boyer
    •  & Andrew Dillin

  • Article |

    This study shows that nematodes without a germ line re-allocate resources to the soma, resulting in elevated proteasome activity, clearance of damaged proteins and increased longevity; this activity is associated with the increased expression of rpn-6 mediated by the transcription factor DAF-16.

    • David Vilchez
    • , Ianessa Morantte
    •  & Andrew Dillin

  • Article |

    This study presents the crystal structure of a RING-type E3 ligase bound to ubiquitin-loaded E2; the structure reveals how ubiquitin binding to E2 leads to changes in the catalytic site, priming it for catalysis by the E3 enzyme.

    • Anna Plechanovová
    • , Ellis G. Jaffray
    •  & Ronald T. Hay

  • Letter |

    An in vivo transposon screen in a pancreatic cancer model identifies frequent inactivation of Usp9x; deletion of Usp9x cooperates with KrasG12D to accelerate rapidly pancreatic tumorigenesis in mice, validating their genetic interaction.

    • Pedro A. Pérez-Mancera
    • , Alistair G. Rust
    •  & David A. Tuveson

  • Letter |

    OTUB1 is an atypical deubiquitinating enzyme which prevents ubiquitin attachment and is important in the DNA damage pathway; structural analysis of OTUB1 in complex with an E2 ubiquitin-conjugating enzyme reveals that the ability of OTUB1 to inhibit ubiquitin chain synthesis is regulated by an allosteric feedback mechanism.

    • Reuven Wiener
    • , Xiangbin Zhang
    •  & Cynthia Wolberger

  • Article |

    The size of COPII vesicles is shown to be controlled by monoubiquitylation, with potential implications for cranio-lenticulo-sutural dysplasia and chylomicron retention disease.

    • Lingyan Jin
    • , Kanika Bajaj Pahuja
    •  & Michael Rape

  • News & Views |

    Correctly dismantling a structure can be as challenging as assembling it. The architecture of the yeast proteasome reveals this enzyme's intricate machinery for protein degradation. See Article p.186

    • Geng Tian
    •  & Daniel Finley

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