Proteolysis

  • Article
    | Open Access

    The plasma metalloprotease ADAMTS13 regulates the platelet-tethering function of von Willebrand factor (VWF) in a shear-dependent manner. Here the authors present the ADAMTS13 crystal structure of the 70kDa N-terminal metalloprotease to spacer domains, and using kinetic measurements they identify a substrate binding induced allosteric mechanism for ADAMTS13, where VWF functions both as an activating cofactor and substrate.

    • Anastasis Petri
    • , Hyo Jung Kim
    •  & James T. B. Crawley
  • Article
    | Open Access

    The cellular functions of poly-SUMO chains of different compositions are not fully understood. Here, the authors characterize Arkadia/RNF111 as a SUMO-targeted ubiquitin ligase that recognizes proteins with hybrid SUMO1-capped SUMO2/3 chains and targets them for proteasomal degradation.

    • Annie M. Sriramachandran
    • , Katrin Meyer-Teschendorf
    •  & R. Jürgen Dohmen
  • Article
    | Open Access

    Pathological cardiac fibrosis is a hallmark of diseases leading to heart failure. Here, the authors used systems genetics to identify a pro-fibrotic gene network regulated by WWP2, a E3 ubiquitin ligase, which orchestrates the nucleocytoplasmic shuttling and transcriptional activity of SMAD2 in the diseased heart.

    • Huimei Chen
    • , Aida Moreno-Moral
    •  & Enrico Petretto
  • 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

    How intracellular cAMP activate PKA is well-characterized, but PKA inactivation remains poorly understood. Here, Rinaldi et al. show that CHIP/HSP70 ubiquitinates the catalytic subunit of PKA, with implications for the human disease spinocerebellar ataxia 16, as patients often have CHIP mutations.

    • Laura Rinaldi
    • , Rossella Delle Donne
    •  & Antonio Feliciello
  • Article
    | Open Access

    Genes encoding protein complex subunits are often dispersed in the genome of eukaryotes, raising the question how these protein complexes assemble. Here, the authors provide evidence that mammalian nuclear transcription complexes are formed co-translationally to ensure specific and functional interactions.

    • Ivanka Kamenova
    • , Pooja Mukherjee
    •  & László Tora
  • 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

    Thrombospondin-1 (THSB1) is a component of the ECM with a role in regulating cancer development and tumour vasculature. Here, the authors show that TGF-beta-induced THBS1 expression contributes to the invasive behaviour of GBM cells and promotes resistance to antiangiogenic therapy partially through interaction with CD47.

    • Thomas Daubon
    • , Céline Léon
    •  & Andréas Bikfalvi
  • Article
    | Open Access

    Ciliogenesis is a complex process requiring hundreds of molecules, although few secreted proteins have been implicated. Here, the authors show that the secreted metalloproteases ADAMTS9 and ADAMTS20 intracellularly regulate ciliogenesis from unique periciliary vesicles with proteolytic activity.

    • Sumeda Nandadasa
    • , Caroline M. Kraft
    •  & Suneel S. Apte
  • Article
    | Open Access

    Membrane elongation is fundamental to autophagy and is controlled by an ubiquitin-conjugating cascade orchestrated by ATG16L1. Here, the authors identify that the E3 ligase Gigaxonin regulates autophagosome formation by controlling ATG16L1 turnover.

    • Aurora Scrivo
    • , Patrice Codogno
    •  & Pascale Bomont
  • Article
    | Open Access

    PTEN is a lipid phosphatase that functions as a dose-dependent tumor suppressor through the PI3K/AKT pathway. Here the authors describe a signaling feedback mechanism where PTEN stability is regulated through transcriptional upregulation of X-linked ubiquitin-specific protease 11 (USP11) via the PI3K/FOXO pathway.

    • Mi Kyung Park
    • , Yixin Yao
    •  & Min Sup Song
  • Article
    | Open Access

    Hippo signaling leads to the phosphorylation of the key transcriptional effector, Yap/Yki, although how Yap/Yki stability is regulated has remained unclear. Here, Sun et al. identify HAUSP/Usp7 as a conserved and clinically relevant regulator of the Hippo pathway that increases Yap/Yki stability.

    • Xiaohan Sun
    • , Yan Ding
    •  & Zizhang Zhou
  • Article
    | Open Access

    Transient aneuploidy enables cells to survive sudden environmental changes before longterm cellular adaptations are established. Here, the authors show that yeast cells respond to the acute loss of Ulp2 SUMO protease by rapid induction of aneuploidy, and reveal predictable long-term adaptation mechanisms that restore euploidy.

    • Hong-Yeoul Ryu
    • , Francesc López-Giráldez
    •  & Mark Hochstrasser
  • Article
    | Open Access

    Ubiquitin and ubiquitin-like modifiers such as SUMO play important roles in several cellular pathways that can become deregulated in cancer. Here the authors describe the structural basis for inhibition of SUMO E1 ligase by the small molecule COH000.

    • Zongyang Lv
    • , Lingmin Yuan
    •  & Shaun K. Olsen
  • Article
    | Open Access

    USP25 is a deubiquitinating enzyme and a positive regulator of Wnt/β-catenin signaling. Here the authors present the crystal structure of USP25 in a tetrameric inactive state and their biochemical and kinetic assays support an USP25 autoinhibitory mechanism that is mediated through a dimer to tetramerization transition.

    • Bing Liu
    • , Marta Sureda-Gómez
    •  & David Reverter
  • 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

    Ischemic reperfusion or nutrient deprivation that produces reactive oxygen species can lead to a loss of muscle contractile function. Here the authors show that glutathionylation of the lysine methyltransferase SMYD2 contributes to degradation or disassembly of sarcomeres.

    • Dhanushka N. P. Munkanatta Godage
    • , Garrett C. VanHecke
    •  & Young-Hoon Ahn
  • Article
    | Open Access

    The Polycomb Repressive-Deubiquitinase (PR-DUB) complex is responsible for the removal of the ubiquitin epigenetic modification from Histone 2A. Here the authors describe the structure of the Drosophila PR-DUB complex, providing new insight into its regulation and how cancer-associated mutations disrupt PR-DUB activity.

    • Martina Foglizzo
    • , Adam J. Middleton
    •  & Peter D. Mace
  • 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

    The autophagy adapter p62/SQSTM1 plays a key role in selective autophagy and also recognizes N-end rule substrates. Here the authors provide molecular insights into p62 N-end rule substrate recognition by solving the structures of the p62 ZZ-domain in complex with various type 1 and type 2 degrons and also show the pH dependent oligomerization of p62.

    • Do Hoon Kwon
    • , Ok Hyun Park
    •  & Hyun Kyu Song
  • Article
    | Open Access

    Ubiquitin modification also occurs in archaea. Here, the authors characterize an archaeal ancestral ubiquitination system, present the crystal structure of the archaeal deubiquitinase Rpn11 from Caldiarchaeum subterraneum bound to ubiquitin and provide insights into evolutionary relationships.

    • Adrian C. D. Fuchs
    • , Lorena Maldoner
    •  & Jörg Martin
  • 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 ribosome-associated quality control complex (RQC) functions to disassemble stalled ribosomes. Here the authors find that the tRNA hydrolase Vms1 is involved in the release of nascent peptide from stalled ribosomes.

    • Olga Zurita Rendón
    • , Eric K. Fredrickson
    •  & Jared Rutter
  • Article
    | Open Access

    Lysine methylation is increasingly being implicated in the modification of non-histone proteins. Here the authors find that the methylation of DNMT1 and E2F1 are recognized by the protein L3MBTL3 and the ubiquitin E3 ligase CRL4DCAF5, which cooperatively target these methylated proteins for ubiquitin-dependent proteolysis.

    • Feng Leng
    • , Jiekai Yu
    •  & Hui Zhang
  • Article
    | Open Access

    Deubiquitinating enzymes (DUBs) are essential to modulate ubiquitin signaling. While known DUBs can be grouped into six families, the authors here present biochemical and structural evidence for a seventh DUB family, defining determinants of substrate specificity for two representative enzymes.

    • Thomas Hermanns
    • , Christian Pichlo
    •  & Kay Hofmann
  • 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

    Ubiquitylation is a dynamic post-translational modification involved in the regulation of numerous cellular processes. Here the authors describe Ub-ProT: a method to measure the length of substrate-attached ubiquitin chains in biological samples, and demonstrate a critical role for chain length in directing substrates to specific cellular pathways.

    • Hikaru Tsuchiya
    • , Daocharad Burana
    •  & Yasushi Saeki
  • Article
    | Open Access

    The U-box ubiquitin ligase UFD-2 is one of the most abundant components of the ubiquitin proteasome system in muscle cells. Here the authors perform in vitro and in vivo experiments and show that UFD-2 has E3 ligase activity and that it ubiquitinates unfolded myosin using the C. elegans myosin chaperone UNC-45 as an adaptor protein.

    • Doris Hellerschmied
    • , Max Roessler
    •  & Tim Clausen
  • 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

    The endoplasmic reticulum (ER) and lysosome are central to cellular stress responses, but it is unclear how ER stress is signaled to lysosomes. Here the authors show that ER stress activates chaperone-mediated autophagy (CMA) via direct phosphorylation of the CMA receptor LAMP2A by the lysosomal p38 MAPK.

    • Wenming Li
    • , Jinqiu Zhu
    •  & Zixu Mao
  • Article
    | Open Access

    MepS is a peptidoglycan (PG) cross-link specific hydrolase needed for cell wall expansion and its cellular levels must be tightly regulated. Here the authors present the structure of the MepS degrading protease Prc bound to its adaptor NlpI and propose a model how the NlpI-Prc complex mediates MepS degradation.

    • Ming-Yuan Su
    • , Nilanjan Som
    •  & Chung-I Chang
  • Article
    | Open Access

    Ubiquitin ligases play critical roles in neuronal connectivity in the brain. Here, Valnegri and colleagues show that ubiquitin ligase RNF8 and ubiquitin-conjugating enzyme UBC13 regulate synapse number in cerebellar granule neurons and rodent cerebellar learning.

    • Pamela Valnegri
    • , Ju Huang
    •  & Azad Bonni
  • Article
    | Open Access

    Deactivated Cas9 fused to transactivation domains can be used to control gene expression, however its presence can prevent rapid switching between different regulatory states. Here the authors generate conditionally degradable dCas9 and Cpf1 proteins for multidimensional control of functional activity.

    • Dirk A. Kleinjan
    • , Caroline Wardrope
    •  & Susan J. Rosser
  • Article
    | Open Access

    So far no enzymatic activity has been attributed to flagellin, the major component of bacterial flagella. Here the authors use bioinformatic analysis and identify a metallopeptidase insertion in flagellins from 74 bacterial species and show that recombinant flagellin and flagellar filaments have proteolytic activity.

    • Ulrich Eckhard
    • , Hina Bandukwala
    •  & Andrew C. Doxey
  • Article
    | Open Access

    Eukaryotic cells rely on the ubiquitin-proteasome system for selective degradation of proteins, a process vital to organismal fitness. Here the authors show that the number of repeats in the polyubiquitin gene is evolutionarily unstable within and between yeast species, and that this variability may tune the cell’s capacity to respond to sudden environmental perturbations.

    • Rita Gemayel
    • , Yudi Yang
    •  & Kevin J. Verstrepen
  • Article
    | Open Access

    Protein stability modulation by E3 ubiquitin ligases is an important layer of functional regulation, but screening for E3 ligase-substrate interactions is time-consuming and costly. Here, the authors take an in silico naïve Bayesian classifier approach to integrate multiple lines of evidence for E3-substrate prediction, enabling prediction of the proteome-wide human E3 ligase interaction network.

    • Yang Li
    • , Ping Xie
    •  & Fuchu He
  • Article
    | Open Access

    HHARI is a RING-in-between-RING (RBR) ubiquitin (Ub) E3 ligase. Here the authors present the crystal structure of HHARI with the UbcH7 ~ Ub thioester intermediate mimetic, which reveals that HHARI binds this E2 ~ Ub in an open conformation and explains the specificity of this cognate RBR E3/E2 pair.

    • Lingmin Yuan
    • , Zongyang Lv
    •  & Shaun K. Olsen