Ubiquitin ligases articles within Nature Communications

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  • Article
    | Open Access

    Gene variants can affect folding and stability of the encoded protein. Here, the authors apply deep mutational scanning to provide genotype-phenotype information for 99% of the possible PRKN variants and reveal mechanistic details on how some variants cause loss-of-function and Parkinsons disease.

    • Lene Clausen
    • , Vasileios Voutsinos
    •  & Rasmus Hartmann-Petersen

  • Article
    | Open Access

    The importance of the SEL1L-HRD1 interaction in vivo was unclear. Here, authors reported that SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex by recruiting the E2 enzyme UBE2J1 and DERLIN to HRD1.

    • Liangguang Leo Lin
    • , Huilun Helen Wang
    •  & Ling Qi

  • Article
    | Open Access

    The T cell receptor signalosome integrates multiple positive and negative regulatory elements to finetune the response and limit harmful inflammation. Here authors show a regulatory cascade of T cell activation, in which DUSP22 negatively regulates UBR2, which is an activator of the kinase Lck via K63 ubiquitination.

    • Ying-Chun Shih
    • , Hsueh-Fen Chen
    •  & Tse-Hua Tan

  • Article
    | Open Access

    Transmembrane E3 ligases are crucial in cellular homeostasis and metabolic regulation. Here, the authors provide the structural details of the ER-resident E3 ligase MARCH6/Doa10, uncovering its unique circular membrane structure and its role in ubiquitylation processes, essential for protein quality control.

    • J. Josephine Botsch
    • , Roswitha Junker
    •  & Bastian Bräuning

  • Article
    | Open Access

    The prevalence and conservation of C-degrons across eukaryotes is unclear. Here, the authors perform an unbiased survey of C-degrons in budding yeast and identify a C-degron pathway of broad specificity operated by the SCFDas1 ubiquitin ligase.

    • Ka-Yiu Edwin Kong
    • , Susmitha Shankar
    •  & Anton Khmelinskii

  • Article
    | Open Access

    Proteolysis-targeting chimeras (PROTACs) offer new avenues for drug development. Here the authors investigate E3 ligases—key to PROTAC function—and identify candidate targets for cancer drivers such as KRAS and EGFR.

    • Yuan Liu
    • , Jingwen Yang
    •  & Leng Han

  • Article
    | Open Access

    Palmitoylation of proteins can have pathophysiological implications. Here, the authors show that palmitoylation enhances the proteasomal degradation of the histone demethylase PHF2, leading to increased lipogenesis and cell proliferation in an SREBP1c dependent manner and further show that PHF2 acts as an E3 ligase of SREBP1c, suppressing the growth of liver cancer cells.

    • Do-Won Jeong
    • , Jong-Wan Park
    •  & Yang-Sook Chun

  • Article
    | Open Access

    Incompletely synthesized nascent polypeptides resulting from ribosome stalling during translation are under surveillance by ribosome-associated quality control. Here, the authors report the molecular mechanism by which the E3 ligase Pirh2 targets the polyalanine tail of aberrant nascent chains for degradation via the C-degron pathway.

    • Xiaolu Wang
    • , Yao Li
    •  & Cheng Dong

  • Article
    | Open Access

    TRIM21 mediates intracellular antibody immunity and is exploited for targeted protein degradation using Trim-Away technology. Here, the authors dissect the ubiquitination requirements for Trim-Away, providing an explanation for how TRIM21 can target diverse substrates for degradation.

    • Leo Kiss
    • , Tyler Rhinesmith
    •  & Leo C. James

  • Article
    | Open Access

    N-degron pathways play an important role in maintaining protein homeostasis. Here, Li et al. demonstrates an additional non-Ac/N-degron pathway, in which N-terminal non-acetylated small residue degrons (Ser, Ala, or Cys) are recognized by CRL2ZER1/ZYG11B and targeted for protein degradation.

    • Yao Li
    • , Yueling Zhao
    •  & Wenyi Mi

  • Article
    | Open Access

    Here the authors show the assembly/disassembly of mammalian SWI/SNF complexes is dynamically regulated by a lysine methylation mechanism involving the demethylase LSD1 and the methyl-lysine reader L3MBTL3, which recognizes SET7-methylated lysines in SMARCC1 and SMARCC2 to target them for CRL4 ubiquitin ligase-mediated proteolysis.

    • Pengfei Guo
    • , Nam Hoang
    •  & Hui Zhang

  • Article
    | Open Access

    The formation of ternary degrader-protein complexes is a key step in the targeted degradation of proteins of interest. Here, the authors explore the structure and dynamics of such complexes applying high-performance computer simulations augmented with experimental data.

    • Tom Dixon
    • , Derek MacPherson
    •  & Jesus A. Izaguirre

  • Article
    | Open Access

    Although ubiquitin ligases are known to control clock protein degradation, their other roles in clock neurons are unclear. Here the authors report that UBR4 promotes export of neuropeptides from the Golgi for axonal trafficking, which is important for circadian clock synchrony in mice and flies.

    • Sara Hegazi
    • , Arthur H. Cheng
    •  & Hai-Ying Mary Cheng

  • Article
    | Open Access

    Attachment of ubiquitin to proteins is tightly regulated and controls many signalling pathways. Here, the authors show that addition of ubiquitin by the RING E3 ligases Arkadia and Ark2C is enhanced by ubiquitin and a charged loop that precedes the RING domain.

    • Andrej Paluda
    • , Adam J. Middleton
    •  & Catherine L. Day

  • Article
    | Open Access

    Entry into S phase of the cell cycle is regulated positively by mitogens and negatively by DNA damage; however, how balance of these signals is achieved is not well known. Here the authors show that the NUCKS1-SKP2- p21/p27 axis integrates this information, where the NUCKS1 transcription factor affects levels of p21/p27 to readout the mitogen:DNA damage balance and regulate S phase entry decision.

    • Samuel Hume
    • , Claudia P. Grou
    •  & Grigory L. Dianov

  • Article
    | Open Access

    SPOP functions as a tumour suppressor in prostate cancer but how the protein is regulated is unclear. Here, the authors identify G3BP1 as a competitive inhibitor of SPOP and show that G3BP1-SPOP axis activates androgen signalling to drive tumorigenesis.

    • Chandrani Mukhopadhyay
    • , Chenyi Yang
    •  & Pengbo Zhou

  • Article
    | Open Access

    The impact of genetic fusions on degrons, which are motifs for ubiquitin-mediated protein degradation, has not been fully explored. Here, the authors analyse fusion genes affecting degrons in pan-cancer genomics data, validate their functional impact and find enrichment for both internal and C-terminal degron losses.

    • Jing Liu
    • , Collin Tokheim
    •  & Wenyi Wei

  • Article
    | Open Access

    Hyperphosphorylated Tau accumulation promotes neurodegeneration in Alzheimer’s disease. Here, the authors screen a miRNA library in Drosophila and identify a conserved ubiquitin ligase that directs Tau for autophagic degradation, uncovering a potential target to treat Tau-mediated neurodegeneration.

    • Manivannan Subramanian
    • , Seung Jae Hyeon
    •  & Kweon Yu

  • Article
    | Open Access

    Haematopoietic stem cells (HSCs) are metabolically quiescent, with balanced myeloid and lymphoid potential. Here the authors show that MAEA is required in HSCs for ubiquitination and downregulation of surface cytokine receptors via autophagy; MAEA loss leads to impaired HSC quiescence and a myeloproliferative disorder.

    • Qiaozhi Wei
    • , Sandra Pinho
    •  & Paul S. Frenette

  • Article
    | Open Access

    Mediators of insulin signalling are targets of cullin-RING ubiquitin ligases (CRL) that mediate protein degradation, but the role of protein degradation in insulin signalling is incompletely understood. Here, the authors identified a glucose-responsive CRL4-COP1-ETV5 proteolytic axis that promotes insulin secretion, and is inhibited under hypoglycemia.

    • Hong Lin
    • , Yuan Yan
    •  & Feng Rao

  • Article
    | Open Access

    The tumor suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF) and itself a target for ubiquitylation. Here, the authors show that TRIP12 mediates branched K11-linked ubiquitylation of FBW7, to regulate its stability and thus abundance of a subset of SCFFBW7 substrates.

    • Omar M. Khan
    • , Jorge Almagro
    •  & Axel Behrens

  • Article
    | Open Access

    Sarcopenia is the age-associated functional decline and atrophy of muscle fibers, and it has been proposed that it might be counteracted by inducing myofiber hypertrophy. Here, the authors show that expression levels of the ubiquitin ligase UBR4 are increased with ageing, and that whilst its genetic ablation rescues muscle atrophy, it is also associated with reduced protein quality and impaired force production in Drosophila and mouse models.

    • Liam C. Hunt
    • , Bronwen Schadeberg
    •  & Fabio Demontis

  • Article
    | Open Access

    NOT4 proteins associate with ribosomes and are required for co-translational quality control in yeast and animals. Here, Bailey et al. show that Arabidopsis NOT4A positively regulates the expression of the nuclear encoded pentatricopeptide repeat (PPR) protein PGR3 and is required for ribosome biogenesis and mRNA translation in the chloroplast.

    • Mark Bailey
    • , Aiste Ivanauskaite
    •  & Daniel J. Gibbs

  • Article
    | Open Access

    Testis-restricted melanoma antigen (MAGE) proteins function as substrate adapters for E3 ubiquitin ligases. Biochemical and structural analyses of MAGE-A11 provide insight into the substrate binding mode of MAGE proteins and enable discovery of potent, cytotoxic inhibitors of MAGE-A11:substrate interaction.

    • Seung Wook Yang
    • , Xin Huang
    •  & Patrick Ryan Potts

  • Article
    | Open Access

    RNF43 is frequently mutated in cancers and negatively regulates Wnt signalling. Here, the authors report that RNF43 phosphorylation at a serine triplet is required for the negative regulation of Wnt signalling and that the phosphorylation of RNF43 suppresses cancer-associated oncogenic RNF43 mutants.

    • Tadasuke Tsukiyama
    • , Juqi Zou
    •  & Shigetsugu Hatakeyama

  • Article
    | Open Access

    5-hydroxythalidomide is a primary thalidomide metabolite generated by the cytochrome P450 isozymes. The reported data, including crystal structure of the 5-hydroxythalidomide-mediated complex of CRBN with SALL4, elucidate how additional hydroxy group of the metabolite enhances the interaction of CRBN with the neosubstrate SALL4.

    • Hirotake Furihata
    • , Satoshi Yamanaka
    •  & Takuya Miyakawa

  • Article
    | Open Access

    p53 is an important tumor suppressor protein which is regulated by the E3 ubiquitin ligase MDM2. Here the authors reveal that DNA damage-induced Ser429 phosphorylation of MDM2 serve to boost the activity of MDM2 homodimer by stabilizing the active E2–ubiquitin complex and promote its self-destruction to enable rapid p53 stabilization.

    • Helge M. Magnussen
    • , Syed F. Ahmed
    •  & Danny T. Huang

  • 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

    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

    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

    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

    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

    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

    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

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