Proteolysis articles within Nature Cell Biology

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  • News & Views |

    Clearing misfolded proteins from the cytoplasm is essential to maintain cellular homeostasis. Now, a parallel clearance system is described that uses the deubiquitylase USP19 to enable secretion of misfolded cytoplasmic proteins when conventional proteasomal degradation is compromised. Misfolding-associated protein secretion (MAPS) has important implications for protein quality control and prion-like transmission.

    • Norbert Volkmar
    • , Emma Fenech
    •  & John C. Christianson

  • News & Views |

    Although known to induce cellular senescence, an important tumour suppressor mechanism, mutation of CDKN1A — the gene encoding p21 (also known as WAF1 or CIP1) — is rare in human cancers. Now, a study reports a previously unappreciated oncogenic effect of p21 overexpression that shapes cancer genome evolution through induction of replication stress.

    • Vasily S. Romanov
    •  & K. Lenhard Rudolph

  • Review Article |

    Yau and Rape discuss recent advances in our understanding of the many variations in ubiquitin chain topology and how these mediate ubiquitin-dependent signalling in the cell.

    • Richard Yau
    •  & Michael Rape

  • News & Views |

    The control of proteasome-mediated protein degradation is thought to occur mainly at the level of polyubiquitylation of the substrate. However, the proteasome can also be regulated directly, as now demonstrated by a study in which DYRK2-mediated phosphorylation of the 19S subunit Rpt3 is found to increase proteasome activity.

    • Jon M. Huibregtse
    •  & Andreas Matouschek

  • News & Views |

    The microcephaly protein, Cep215, contributes to the engagement of duplicated centrioles in interphase. Now two distinct pools of Cep215 at centrosomes are identified, one bound to Cep68 and the other to pericentrin. Plk1-mediated degradation of Cep68 and separase-mediated cleavage of pericentrin release both pools of Cep215, thereby promoting centriole disengagement.

    • Andrew M. Fry

  • News & Views |

    Protein quality control systems protect cells from proteotoxicity caused by the accumulation of aberrantly folded polypeptides. The Rsp5 ubiquitin ligase (mammalian homologue Nedd4) is now identified as a major constituent of a clearance pathway that degrades misfolded cytosolic proteins after exposure to heat.

    • Thomas Sommer
    • , Annika Weber
    •  & Ernst Jarosch

  • Article |

    How misfolded proteins are extracted from the endoplasmic reticulum (ER) for degradation remains unclear. Sommer and colleagues demonstrate that following assembly into the HRD ligase complex, Der1 forms oligomers in the ER membrane and enables extraction of proteins from the ER lumen.

    • Martin Mehnert
    • , Thomas Sommer
    •  & Ernst Jarosch

  • Article |

    The stability of the PTEN tumour suppressor protein is regulated by polyubiquitylation. Ma and colleagues identify USP13 as an enzyme reversing polyubiquitylation of PTEN, leading to PTEN stabilization and tumour suppression.

    • Jinsong Zhang
    • , Peijing Zhang
    •  & Li Ma

  • News & Views |

    Cytoplasmic compartments containing misfolded proteins targeted for degradation, named Q-bodies, have been identified. Q-body formation is a dynamic process that actively manages the metastable state of the protein fold through small heat shock proteins and the Hsp70–Hsp90–Hsp110 proteostasis system to promote cellular fitness under both physiological and stress conditions.

    • Daniela Martino Roth
    •  & William E. Balch

  • Article |

    The RAS-like GTPase RALB mediates cellular responses to nutrient availability or viral infection by engaging two distinct exocyst complex proteins: EXO84 to modulate autophagy and SEC5 to regulate innate immune signalling. Sablina and colleagues find that whereas ubiquitylation of RALB at K47 promotes its interaction with SEC5, the de-ubiquitylase USP33 switches RALB to the EXO84–beclin complex to promote autophagy during nutrient starvation.

    • Michal Simicek
    • , Sam Lievens
    •  & Anna A. Sablina

  • Article |

    Quality control of misfolded proteins is thought to involve proteasome-dependent degradation or, if this fails, sequestration into inclusion bodies. Frydman and colleagues reveal the existence of endoplasmic-reticulum-associated structures, termed Q-bodies, that concentrate misfolded proteins in a chaperone-dependent manner before degradation.

    • Stéphanie Escusa-Toret
    • , Willianne I. M. Vonk
    •  & Judith Frydman

  • Letter |

    The segregase Cdc48 (also called p97 or VCP) extracts ubiquitylated proteins from their environment. Jentsch and colleagues demonstrate that Cdc48 binds SUMOylated Rad52, and removes Rad52 and the recombinase Rad51 from DNA to restrict spontaneous recombination.

    • Steven Bergink
    • , Tim Ammon
    •  & Stefan Jentsch

  • News & Views |

    To ensure proper attachment of all chromosomes to the spindle, PLK1 has to associate with kinetochores during prometaphase and must be released from these sites before sister chromatid separation can begin. The monoubiquitylation of PLK1 by the ubiquitin ligase CUL3–KLHL22 is now identified as a critical step in promoting the release of PLK1 from kinetochores, pushing non-proteolytic ubiquitylation into the limelight of cell division research.

    • Colleen A. McGourty
    •  & Michael Rape

  • Article |

    The dynamic localization of PLK1 to kinetochores is required for faithful chromosome segregation. Peter, Sumara and colleagues demonstrate that a KHL22-containing E3 ligase mediates degradation-independent removal of PLK1 from kinetochores to ensure satisfaction of the spindle assembly checkpoint and proper mitotic progression.

    • Jochen Beck
    • , Sarah Maerki
    •  & Izabela Sumara

  • Article |

    The mTORC1 complex promotes protein translation and cell growth, whereas mTORC2 promotes survival. The Tel2 and Tt1 proteins belong to both complexes. Bassermann and colleagues demonstrate that following growth-factor deprivation, casein kinase 2 mediates phosphorylation of Tel2 and Tt1, specifically in the mTORC1 complex, to target them for degradation by the SCFFbxo9 ubiquitin ligase. This mechanism inactivates mTORC1 and activates mTORC2 and Akt signalling to promote survival of multiple myeloma cells.

    • Vanesa Fernández-Sáiz
    • , Bianca-Sabrina Targosz
    •  & Florian Bassermann

  • News & Views |

    The transforming growth factor (TGF-β) pathway is regulated by ubiquitin-mediated proteolysis at different levels. Two studies now identify deubiquitinating enzymes (DUBs) for the TGF-β type I receptor. Both ubiquitin-specific peptidase-4 (USP4) and -15 (USP15) extend the life of activated receptors against the negative pressure of receptor-ubiquitinating complexes, but through distinct modes of action.

    • Kamna Aggarwal
    •  & Joan Massagué

  • Article |

    Wu and colleagues delineate an mTORC2-dependent cell migration pathway. They show that stimulation of the Gα12 protein subunit induces the ARAF/ERK-mediated expression of the RFFL E3 ubiquitin ligase. RFFL, in turn, targets the inhibitory PRR5L subunit of the mTORC2 complex for ubiquitylation and degradation, enabling mTORC2 to phosphorylate PKC-δ and promote cell migration.

    • Xiaoqing Gan
    • , Jiyong Wang
    •  & Dianqing Wu

  • Article |

    Integrin internalization through the endosomal pathway can lead either to recycling back to the surface or to lysosomal degradation. Faessler and colleagues now show that, following internalization, β1 integrins are bound by sorting nexin 17 in early endosomes to prevent integrin degradation in lysosomes and to promote surface recycling.

    • Ralph Thomas Böttcher
    • , Christopher Stremmel
    •  & Reinhard Fässler

  • Article |

    The SCF ubiquitin ligase subunit Fbxw7 is a tumour suppressor that is mutated in many cancers. Pagano and colleagues now show that in multiple myeloma, Fbxw7α instead functions as a pro-survival factor by activating the NF-κB pathway through the ubiquitin-mediated degradation of p100, an NF-κB pathway inhibitor.

    • Luca Busino
    • , Scott E. Millman
    •  & Michele Pagano

  • Article |

    Cyclin B is targeted for proteasome-mediated degradation by the E3 ligase APC/C, which is thought to generate polyubiquitin chains for the degradation of mitotic substrates. King and colleagues now demonstrate in Xenopus laevis extracts that multiple monoubiquitylation events are sufficient to target cyclin B1 for degradation.

    • Nevena V. Dimova
    • , Nathaniel A. Hathaway
    •  & Randall W. King

  • Letter |

    Oxygen levels regulate the stability of the transcription factor HIF-1 through the action of prolyl hydroxylases and the VHL ubiquitin ligase. Sharp and colleagues now identify a protein complex in which the Ajuba LIM-domain protein LIMD1 brings together prolyl hydroxylases and VHL to ensure efficient degradation of HIF-1.

    • Daniel E. Foxler
    • , Katherine S. Bridge
    •  & Tyson V. Sharp

  • Resource |

    Improperly folded proteins are targeted for destruction through the endoplasmic-reticulum-associated degradation pathway (ERAD). Kopito and colleagues present a high-resolution interaction analysis of the ERAD system in combination with functional genomics, and identify new ERAD components.

    • John C. Christianson
    • , James A. Olzmann
    •  & Ron R. Kopito

  • Article |

    Wallerian degeneration occurs in axons following cutting or crush injuries; however, the molecular mechanisms that regulate this process remain elusive. Araki and colleagues find that the ubiquitin ligase ZNRF1 promotes Wallerian degeneration by ubiquitylating AKT, which leads to increased GSK3B activity and subsequent inhibition of the tubulin-binding protein CRMP2.

    • Shuji Wakatsuki
    • , Fuminori Saitoh
    •  & Toshiyuki Araki

  • Letter |

    Caspase 8 is known to suppress necroptosis, but its relevant target protein was unknown. Ting and colleagues show that caspase 8 cleaves the deubiquitylase CYLD to inhibit necroptosis and promote cell survival.

    • Marie Anne O’Donnell
    • , Eva Perez-Jimenez
    •  & Adrian T. Ting

  • Letter |

    The p97 AAA+ ATPase (also known as VCP) functions in various ubiquitin-regulated processes. Ramadan and colleagues now find that p97 is recruited to sites of DNA damage by Lys-48-linked ubiquitin chains, which are formed in a process mediated by RNF8. p97 then removes Lys-48–ubiquitin conjugates and promotes recruitment of DNA-repair factors.

    • Mayura Meerang
    • , Danilo Ritz
    •  & Kristijan Ramadan

  • News & Views |

    Misfolded proteins are potentially toxic and are therefore subjected to highly selective degradation by the ubiquitin–proteasome system. The identification of the Hul5 ubiquitin ligase as a major mediator of such 'quality-control' ubiquitylation following heat shock raises new questions about the design of these pathways.

    • Daniel Finley

  • Letter |

    In the TGFβ pathway, receptor-activated SMADs (R-SMADs) associate with SMAD4 to regulate transcription. Piccolo and colleagues reveal that the deubiquitylase USP15 is required for TGFβ responses by reversing R-SMAD ubiquitylation and thereby promoting the retention of the SMAD complex at promoters.

    • Masafumi Inui
    • , Andrea Manfrin
    •  & Stefano Piccolo

  • Article |

    Non-enveloped viruses such as SV40 are transported from the extracellular space into the host cell nucleus through a pathway involving endocytosis, trafficking to the endoplasmic reticulum (ER) lumen, transport across the ER membrane to the cytoplasm, and subsequent nuclear import. Helenius and colleagues provide insight into how SV40 escapes from the ER by showing that viral proteins interact with components of the host ER-associated degradation machinery (ERAD). These interactions are crucial for translocation of SV40 into the cytoplasm and infectivity.

    • Roger Geiger
    • , Daniel Andritschke
    •  & Ari Helenius

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