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UbiQ news: publication highlights Aug 2016

By

Wieger Rupert

 

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August 22, 2016
 

publication highlights

publications that have caught our interest


Our publication highlights newsletter serves to highlight some of the recent reported work in the Ubiquitin Proteasome Field.

 
Autophagic Turnover of Inactive 26S Proteasomes in Yeast Is Directed by the Ubiquitin Receptor Cue5 and the Hsp42 Chaperone.
Richard S. Marshall, Fionn McLoughlin and Richard D. Vierstra. Cell Reports , 2016, 16, 1717 - 1732

highlights
  • the yeast 26S proteasome is degraded by Atg8-mediated autophagy
  • nitrogen starvation and inactivation stimulate proteaphagy via distinct pathways
  • proteasome inhibition is accompanied by extensive ubiquitylation of the complex
  • proteaphagy engages the Cue5 autophagy receptor and the Hsp42 chaperone
summary
The autophagic clearance of 26S proteasomes (proteaphagy) is an important homeostatic mechanism within the ubiquitin system that modulates proteolytic capacity and eliminates damaged particles. In the above paper, Vierstra and co-workers report two proteaphagy routes in yeast that respond to either nitrogen starvation or particle inactivation. Whereas the core autophagic machineries required for Atg8 lipidation and vesiculation are essential for both routes, the upstream Atg1 kinase participates only in starvation-induced proteaphagy. Following inactivation, 26S proteasomes become extensively modified with ubiquitin. Although prior studies with Arabidopsis implicated RPN10 in tethering ubiquitylated proteasomes to ATG8 lining the autophagic membranes, yeast proteaphagy employs the evolutionarily distinct receptor Cue5, which simultaneously binds ubiquitin and Atg8. Proteaphagy of inactivated proteasomes also requires the oligomeric Hsp42 chaperone, suggesting that ubiquitylated proteasomes are directed by Hsp42 to insoluble protein deposit (IPOD)-type structures before encapsulation. Together, Cue5 and Hsp42 provide a quality control checkpoint in yeast directed at recycling dysfunctional 26S proteasomes.
read all in Cell Reports
 
The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity.
Rune Busk Damgaard, Jennifer A. Walker, Paola Marco-Casanova, Neil V. Morgan, Hannah L. Titheradge, Paul R. Elliott, Duncan McHale, Eamonn R. Maher, Andrew N.J. McKenzie and David Komander Cell  2016, In Press DOI: 10.1016/j.cell.2016.07.019


highlights
  • mutation of OTULIN causes OTULIN-related autoinflammatory syndrome (ORAS) in humans
  • anti-TNF treatment reverses inflammation in ORAS patient and OTULIN-deficient mice
  • OTULIN deficiency deregulates M1-polyUb signaling and causes sterile inflammation
  • loss of OTULIN has cell-type-specific effects on LUBAC abundance and signaling
summary
Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains poorly understood. In the above paper, David Komander and co-workers show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN was found to cause a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS). Four independent OTULIN mouse models revealed that OTULIN deficiency in immune cells results in cell-type-specific effects, ranging from over-production of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells. Remarkably, treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes. Hence, OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis.
read all in Cell
 
Divergence in Ubiquitin Interaction and Catalysis among the Ubiquitin-Specific Protease Family Deubiquitinating Enzymes
Adam H. Tencer, Qin Liang and Zhihao Zhuang Biochemistry 2016, In Press DOI: 10.1021/acs.biochem.6b00033

summary
Deubiquitinating enzymes (DUBs) are responsible for reversing mono- and polyubiquitination of proteins and play essential roles in numerous cellular processes. Close to 100 human DUBs have been identified and are classified into five families, with the ubiquitin-specific protease (USP) family being the largest (>50 members). The binding of ubiquitin (Ub) to USP is strikingly different from that observed for the DUBs in the ubiquitin C-terminal hydrolase (UCH) and ovarian tumor domain protease (OTU) families. In the above paper, Zhihao Zhuang and co-workers generated a panel of mutant ubiquitins and used them to probe the ubiquitin’s interaction with a number of USPs. Their results revealed a remarkable divergence of USP–Ub interactions among the USP catalytic domains. Their double-mutant cycle analysis targeting the ubiquitin residues located in the tip, the central body, and the tail of ubiquitin also demonstrated different crosstalk among the USP–Ub interactions. This work uncovered intriguing divergence in the ubiquitin-binding mode in the USP family of DUBs and raises the possibility of targeting the ubiquitin-binding hot spots on USPs for selective inhibition of USPs by small molecule antagonists.
read all in Biochemistry
 
Ubiquitin C-terminal hydrolase L1 (UCH-L1): structure, distribution and roles in brain function and dysfunction
Paul Bishop, Dan Rocca and Jeremy M. Henley Biochemical Journal 2016, 473, 2453-2462


summary
Ubiquitin C-terminal hydrolase L1 (UCH-L1) is an extremely abundant protein in the brain where, remarkably, it is estimated to make up 1–5% of total neuronal protein. Although it comprises only 223 amino acids it has one of the most complicated 3D knotted structures yet discovered. Beyond its expression in neurons UCH-L1 has only very limited expression in other healthy tissues but it is highly expressed in several forms of cancer. Although UCH-L1 is classed as a deubiquitinating enzyme (DUB) the direct functions of UCH-L1 remain enigmatic and a wide array of alternative functions has been proposed. UCH-L1 is not essential for neuronal development but it is absolutely required for the maintenance of axonal integrity and UCH-L1 dysfunction is implicated in neurodegenerative disease. The above review by Henley and co-workers reports on the latest insights in the properties of UCH-L1, and how understanding its complex structure can provide new insights into its roles in neuronal function and pathology.
read all in Biochemical Journal
 
Total Chemical Synthesis of SUMO Proteins
Oleg Melnyk and Jérôme Vicogne. Tetrahedron Letters 2016, In Press
DOI: 
10.1016/j.tetlet.2016.08.035

highlights
  • a central cysteine in SUMO facilitates its synthesis by native chemical ligation
  • SUMO-1 peptide protein conjugates were synthesized in one-pot
  • human SUMO-2/3 were synthesized by sequential ligations

summary
The total chemical synthesis of proteins is a useful alternative to living systems for accessing small proteins. Significant progresses have been made these recent years in the design of novel chemoselective amide bond ligation chemistries that can be integrated in efficient peptide segment assembly strategies. These methods are used to tackle challenging protein targets that are not easily attainable using classical recombinant techniques. The above digest article by Oleg Melnyk and Jérôme Vicogne focuses on the latest advances in the total chemical synthesis of small ubiquitin-like modifier (SUMO) proteins and SUMO peptide protein conjugates.
read all in Tetrahedron Letters
 

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