Proteasome

  • Article
    | Open Access

    TOP1 resolves DNA supercoils by forming cleavage complexes (TOP1cc) that are trapped by TOP1 inhibitors. Here the authors provide insights into the mechanistic understanding of TOP1cc PARylation, showing that inhibition of PARG results in stabilization of TOP1cc PARylation that blocks the proteasomal degradation of TOP1cc.

    • Yilun Sun
    • , Jiji Chen
    •  & Yves Pommier
  • Article
    | Open Access

    Autophagy and the ubiquitin–proteasome system (UPS) are cellular quality control processes, but their coordination remains unclear. Here, the authors show that branched ubiquitination of VPS34 functions as a switch between UPS and autophagy and has an important role in lipid metabolism in the liver.

    • Yu-Hsuan Chen
    • , Tzu-Yu Huang
    •  & Ruey-Hwa Chen
  • Article
    | Open Access

    Muscle atrophy is associated with ageing, but the underlying molecular mechanisms are not well understood. Here, they authors show that ablation of the E3 ubiquitin ligase Mib1 is important for myofibre maintenance via a mechanism that involves targeting and degradation of Actn3, and that Mib1 ablation in mice induces muscle atrophy which can be rescued by knockown of Actn3 expression.

    • Ji-Yun Seo
    • , Jong-Seol Kang
    •  & Young-Yun Kong
  • Article
    | Open Access

    Plasmodium falciparum secretes extracellular vesicles (EVs) while growing inside red blood cells (RBCs). Here the authors show that these EVs contain assembled and functional 20S proteasome complexes that remodel the cytoskeleton of naïve human RBCs, priming the RBCs for parasite invasion.

    • Elya Dekel
    • , Dana Yaffe
    •  & Neta Regev-Rudzki
  • Article
    | Open Access

    The proteasome activator PA28αβ affects MHC class I antigen presentation by associating with immunoproteasome core particles (iCPs). Cryo-EM structures of the mammalian PA28αβ -iCP immunoproteasome and free iCP, combined with cross-linking data, reveal the complex architecture and suggest a distinct immunoproteasome activation mechanism.

    • Jinhuan Chen
    • , Yifan Wang
    •  & Yao Cong
  • Article
    | Open Access

    Immune cells express immunoproteasomes (i20S), which bind to specialized regulators, contain different catalytic subunits and generate immunogenic peptides. HDX-MS—based assessment of the differences between the conformational dynamics of standard and i20s reveals specific, allosteric changes in i20S and upon regulator binding.

    • Jean Lesne
    • , Marie Locard-Paulet
    •  & Julien Marcoux
  • Article
    | Open Access

    Endothelial cell (EC) dysfunction and inflammation contribute to plaque destabilization in atherosclerosis, increasing the risk of thrombotic events. Here, the authors show that epsin promotes EC inflammation via a mechanism involving IP3R1 degradation, and that deletion of epsin in the endothelium prevents EC dysfunctoin and atherosclerosis in mice.

    • Yunzhou Dong
    • , Yang Lee
    •  & Hong Chen
  • Article
    | Open Access

    Human papilloma virus (HPV) E7 protein destabilizes the retinoblastoma protein (Rb) by inducing its ubiquitination in cervical cancer cells, however proteasomal degradation requires cleavage of Rb after Lys 810 and so far it has been unclear how Rb cleavage contributes to its degradation. Here, the authors combine cell based and in vitro assays and show that calpain cleavage exposes a region in Rb that is recognized by the proteasome, leading to rapid proteolysis of Rb, whereas the proteasome cannot initiate degradation efficiently on full-length Rb.

    • Takuya Tomita
    • , Jon M. Huibregtse
    •  & Andreas Matouschek
  • Article
    | Open Access

    The Lys48-linked polyubiquitin-mediated proteasomal degradation in yeast depends on Cdc48 and its cofactors Ufd1 and Npl4. Here, the authors present crystal structures of Npl4 bound to Lys48-linked diubiquitin and the Npl4-binding motif of Ufd1, providing insights into the reaction mechanism of the Cdc48- Ufd1/Npl4 complex.

    • Yusuke Sato
    • , Hikaru Tsuchiya
    •  & Shuya Fukai
  • Article
    | Open Access

    Targeted protein degradation (TPD) is a promising strategy for drug development. In this proof-of-concept study, the authors use telaprevir, which binds hepatitis C virus (HCV) NS3/4A protease, to target the protease for protein degradation, and show inhibition of wildtype as well as drug resistant HCV.

    • Mélissanne de Wispelaere
    • , Guangyan Du
    •  & Priscilla L. Yang
  • Article
    | Open Access

    Regeneration after injury in the Drosophila intestine involves early activation of intestinal stem cells (ISCs) and subsequent return to quiescence. Here the authors show that return to quiescence by ISCs involves BMP Type I receptor Tkv protein stabilization along with AWD mediated internalization into endocytic vesicles.

    • Xiaoyu Tracy Cai
    • , Hongjie Li
    •  & Heinrich Jasper
  • Article
    | Open Access

    Exosomes are intercellular signaling vesicles created by fusion of multivesicular bodies (MVBs) and the plasma membrane (PM), but secretory regulation is ill-defined. Song et al. show that KIBRA controls exosome secretion by protecting Rab27a from proteasomal degradation, promoting MVB-PM docking.

    • Lin Song
    • , Shi Tang
    •  & Yifeng Du
  • Article
    | Open Access

    Protein NEDDylation increases upon proteotoxic stress but the function of this response remains to be elucidated. Here, the authors show that NEDDylation contributes to the cellular defence against proteotoxicity by promoting nuclear protein aggregation and protecting the ubiquitin proteasome system.

    • Chantal M. Maghames
    • , Sofia Lobato-Gil
    •  & Dimitris P. Xirodimas
  • Article
    | Open Access

    The ubiquitin-like modifier FAT10 is composed of two ubiquitin-like domains (UBDs). Here the authors present the FAT10 UBD structures and show that the unstructured FAT10 N-terminal heptapeptide together with the poor stability of FAT10 facilitate the rapid proteasomal targeting of FAT10 along with its substrates.

    • Annette Aichem
    • , Samira Anders
    •  & Silke Wiesner
  • Article
    | Open Access

    Proteasomal ATPases contain functionally important coiled-coil (CC) domains, the mechanistic role of which is not fully understood. Here, the authors provide evidence for three distinct CC conformations, showing that CC conformational changes enable ATPases to switch between active and resting states.

    • Aaron Snoberger
    • , Evan J. Brettrager
    •  & David M. Smith
  • Article
    | Open Access

    The proteome-wide characterization of proteostasis depends on robust approaches to determine protein half-lives. Here, the authors improve the accuracy and precision of mass spectrometry-based quantification, enabling reliable protein half-life determination in several non-dividing cell types.

    • Toby Mathieson
    • , Holger Franken
    •  & Mikhail M. Savitski
  • Article
    | Open Access

    Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that mark proteins for degradation, but there is a current lack of knowledge about their distinct functions and substrates. Here, the authors elucidate the cellular roles and substrates of these polymerases using comparative functional and proteomics analyses of tankyrase knockout cell lines.

    • Amit Bhardwaj
    • , Yanling Yang
    •  & Susan Smith
  • Article
    | Open Access

    Soluble misfolded proteins that fail to be degraded by the ubiquitin proteasome system (UPS) are redirected to autophagy via specific adaptors, such as p62. Here the authors show that p62 recognises N-degrons in these proteins, acting as a N-recognin from the proteolytic N-end rule pathway, and targets these cargos to autophagosomal degradation.

    • Hyunjoo Cha-Molstad
    • , Ji Eun Yu
    •  & Bo Yeon Kim
  • Article
    | Open Access

    The proteasome regulates several important cellular processes and has been identified as a target for therapeutic interventions. Here the authors map the conformational and energy landscape of the 26S proteasome upon Oprozomib binding and uncover long-range allosteric effects that control the dynamic behaviour of the proteasome.

    • David Haselbach
    • , Jil Schrader
    •  & Holger Stark
  • Article
    | Open Access

    Ubiquitin (Ub) receptors are responsible for the recognition of ubiquitylated proteins. Here the authors describe the crystal structure of the ubiquitylated form of the Ub-receptor Rpn10, which suggest that ubiquitylation of Rpn10 promotes its dissociation from the proteasome.

    • Tal Keren-Kaplan
    • , Lee Zeev Peters
    •  & Gali Prag
  • Article
    | Open Access

    The expression of the oncogene Myc is carefully controlled and dysregulation often leads to cancer. Here, the authors describe an E3 ligase for Myc—ELL—and show that it likely controls the ubiquitination and degradation of Myc.

    • Yu Chen
    • , Chi Zhou
    •  & Wuhan Xiao
  • Article
    | Open Access

    The proteasome, an essential molecular machine, is a threonine protease, but the evolution and the components of its proteolytic centre are unclear. Here, the authors use structural biology and biochemistry to investigate the role of proteasome active site residues on maturation and activity.

    • Eva M. Huber
    • , Wolfgang Heinemeyer
    •  & Michael Groll
  • Article
    | Open Access

    The proteasome plays a key role in proteostasis by mediating the degradation of ubiquitinated substrates. Here the authors show that an open-gate mutant of the proteasome is hyperactive towards a subset of substrates and can effectively delay the accumulation of toxic protein aggregates.

    • Won Hoon Choi
    • , Stefanie A. H. de Poot
    •  & Min Jae Lee
  • Article
    | Open Access

    The 26S proteasome contains a hexamer of ATPase subunits, which binds, unfolds and translocates substrates in an ATP-dependent manner. Kim et al. use FRET to show that ATP binding preferentially occurs at neighbouring subunits of the hexamer, and identify two allosteric systems that coordinate translocation.

    • Young-Chan Kim
    • , Aaron Snoberger
    •  & David M. Smith
  • Article
    | Open Access

    Small archaeal ubiquitin-like modifiers (SAMPs) have been hypothesized to be part of an ancestral version of the ubiquitin-proteasome system. Here, Anjum et al. identify a SAMP homologous to the eukaryotic ubiquitin-related modifier-1 and show that it is processed by the 20S core proteasome in S. acidocaldarius.

    • Rana S. Anjum
    • , Sian M. Bray
    •  & Nicholas P. Robinson
  • Article
    | Open Access

    The proteasome is a highly regulated complex fundamental for cell homeostasis and a target for cancer therapy. Here the authors use cryo-EM and single-particle analysis to obtain a detailed map of the interactions between each active sites of the core 20S proteasome and the irreversible inhibitor AdaAhx3L3VS.

    • Paula C.A. da Fonseca
    •  & Edward P. Morris
  • Article
    | Open Access

    Proteasomes digest intracellular proteins into peptides that are then presented to lymphocytes as antigens. Here the authors show that a thymic epithelium-specific proteasome subunit cuts model proteins in a pattern favouring their weak binding to T cell receptor, and thus T cell positive selection.

    • Katsuhiro Sasaki
    • , Kensuke Takada
    •  & Shigeo Murata
  • Article |

    REGγ, a proteasome activator, is associated with multiple oncogenic pathways in human cancers and can promote the degradation of multiple proteins including p53. Here the authors highlight a potential role for REGγ in skin cancer and propose a molecular mechanism linking p38 MAPK and Wnt signalling.

    • Lei Li
    • , Yongyan Dang
    •  & Xiaotao Li
  • Article |

    Mutations in the gene encoding DJ-1 are associated with early-onset familial forms of Parkinson’s disease, and several different molecular functions have been attributed to this protein. Moscovitz et al.show that DJ-1 physically binds the 20S proteasome and inhibits its degradation activity.

    • Oren Moscovitz
    • , Gili Ben-Nissan
    •  & Michal Sharon
  • Review Article |

    Proteins are subject to continuous and complex quality-control mechanisms, which ensure integrity of the proteome. Vilchez et al.review how a demise in these processes, collectively referred to as proteostasis, is linked to organismal ageing and the development of age-associated diseases.

    • David Vilchez
    • , Isabel Saez
    •  & Andrew Dillin
  • Article |

    Increasing the activity of the proteasome can prevent the accumulation of protein aggregates within the cell. Han et al.show that nanoparticle-mediated delivery of purified proteasomes to cells reduces proteotoxic stress resulting from tau overexpression, and prevents to accumulation of tau aggregates.

    • Dong Hoon Han
    • , Hee-Kyung Na
    •  & Min Jae Lee
  • Article
    | Open Access

    Biogenesis of the primary cilium begins after cell cycle exit, but the regulatory steps for its formation are poorly defined. Here the authors show that proteasome-mediated removal of the ciliogenesis inhibitor, trichoplein, from mother centrioles initiates the first step of ciliogenesis.

    • Kousuke Kasahara
    • , Yoshitaka Kawakami
    •  & Masaki Inagaki
  • Article |

    Nck1/2 adaptor proteins control the assembly and activity of protein complexes that promote actin polymerization. Buvall et al.show that Nck1 abundance is regulated by the E3 ubiquitin ligase c-Cbl, which competes for Nck binding with the actin-binding protein synaptopodin in podocytes.

    • Lisa Buvall
    • , Priyanka Rashmi
    •  & Peter Mundel
  • Article |

    The 26S proteasome comprises over 33 different subunits that must be correctly assembled by dedicated chaperones for efficient protein degradation. Here the authors find that general chaperone proteins are also vital for proper proteasome assembly.

    • Takashi Akahane
    • , Kazutaka Sahara
    •  & Shigeo Murata
  • Article |

    Soluble cytosolic proteins can be degraded in lysosomes by chaperone-mediated autophagy, however, the current method to measure this process requires isolation of lysosomes. Now, a fluorescent reporter is described that can measure this type of autophagy in intact cells.

    • Hiroshi Koga
    • , Marta Martinez-Vicente
    •  & Ana Maria Cuervo
  • Article |

    Rad23 accompanies ubiquitinated substrates to the proteasome for destruction but manages to avoid degradation. In this study, Fishbainet al.show that Rad23 escapes because it lacks an effective initiation region; therefore, the proteasome is unable to engage the protein and unfold it.

    • Susan Fishbain
    • , Sumit Prakash
    •  & Andreas Matouschek