A Systematic Protein Turnover Map for Decoding Protein Degradation

Christiano, Romain; Arlt, Henning; Kabatnik, Sonja; Mejhert, Niklas; Lai, Zon Weng; Farese, Robert V.; Walther, Tobias C.

doi:10.1016/j.celrep.2020.108378

Cited by 24 publications

(23 citation statements)

References 36 publications

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“…This is consistent with the idea that GID regulates protein turnover in metabolic transitions or in response to stress ( Melnykov et al., 2019 ) and highlights how colony-based proteome profiling can reveal conditional phenotypes. Metabolic heterogeneity of colonies also complicates direct comparison with pulse SILAC proteomic profiling of the UPS ( Christiano et al., 2020 ). GID-dependent turnover of Mdh2, Ydr222w, and several GID subunits in log-phase cultures ( Figure 5 B) suggests that the GID E3 is also active under steady-state conditions, consistent with previous observations ( Menssen et al., 2018 ).…”

Section: Resultsmentioning

confidence: 99%

“…The proteomic approach applied here, although arguably more laborious compared with mass spectrometry-based proteomics ( Christiano et al., 2020 ), has several advantages. First, because protein abundance and stability were measured in yeast colonies, which consist of metabolically heterogeneous populations ( Cáp et al., 2012 ), our proteome profiling is sampling multiple environmental conditions in one experiment.…”

Section: Discussionmentioning

confidence: 99%

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Timer-based proteomic profiling of the ubiquitin-proteasome system reveals a substrate receptor of the GID ubiquitin ligase

et al. 2021

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Summary Selective protein degradation by the ubiquitin-proteasome system (UPS) is involved in all cellular processes. However, the substrates and specificity of most UPS components are not well understood. Here we systematically characterized the UPS in Saccharomyces cerevisiae . Using fluorescent timers, we determined how loss of individual UPS components affects yeast proteome turnover, detecting phenotypes for 76% of E2, E3, and deubiquitinating enzymes. We exploit this dataset to gain insights into N-degron pathways, which target proteins carrying N-terminal degradation signals. We implicate Ubr1, an E3 of the Arg/N-degron pathway, in targeting mitochondrial proteins processed by the mitochondrial inner membrane protease. Moreover, we identify Ylr149c/Gid11 as a substrate receptor of the glucose-induced degradation-deficient (GID) complex, an E3 of the Pro/N-degron pathway. Our results suggest that Gid11 recognizes proteins with N-terminal threonines, expanding the specificity of the GID complex. This resource of potential substrates and relationships between UPS components enables exploring functions of selective protein degradation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Timer-based proteomic profiling of the ubiquitin-proteasome system reveals a substrate receptor of the GID ubiquitin ligase

et al. 2021

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“…For example, transmission of low-frequency bursts along the PFs may help tuning the molecular layer with cortical low-frequency oscillatory inputs on the theta-band 98 , 99 , with reflections on circuit synchronization and on the induction of long-term synaptic plasticity. These potential consequences remain to be investigated using advanced recording techniques and large-scale circuit simulations 39 , 100 .…”

Section: Discussionmentioning

confidence: 99%

“…Those models have shown the impact of increasing or decreasing SC transmission strength under the assumption of linear rate coding and in the absence of short-term plasticity 36 , 37 . However, it is now clear from several studies that detailed membrane and synaptic dynamics are critical to understand the way a neural circuit operates 38 , 39 . Therefore, we have recorded electroresponsive and synaptic dynamics of SC and used them to generate detailed computational models through well-defined workflows for model construction and validation 34 , 35 , 40 .…”

Section: Introductionmentioning

confidence: 99%

Stellate cell computational modeling predicts signal filtering in the molecular layer circuit of cerebellum

Rizza

Locatelli

Masoli

et al. 2021

Sci Rep

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The functional properties of cerebellar stellate cells and the way they regulate molecular layer activity are still unclear. We have measured stellate cells electroresponsiveness and their activation by parallel fiber bursts. Stellate cells showed intrinsic pacemaking, along with characteristic responses to depolarization and hyperpolarization, and showed a marked short-term facilitation during repetitive parallel fiber transmission. Spikes were emitted after a lag and only at high frequency, making stellate cells to operate as delay-high-pass filters. A detailed computational model summarizing these physiological properties allowed to explore different functional configurations of the parallel fiber—stellate cell—Purkinje cell circuit. Simulations showed that, following parallel fiber stimulation, Purkinje cells almost linearly increased their response with input frequency, but such an increase was inhibited by stellate cells, which leveled the Purkinje cell gain curve to its 4 Hz value. When reciprocal inhibitory connections between stellate cells were activated, the control of stellate cells over Purkinje cell discharge was maintained only at very high frequencies. These simulations thus predict a new role for stellate cells, which could endow the molecular layer with low-pass and band-pass filtering properties regulating Purkinje cell gain and, along with this, also burst delay and the burst-pause responses pattern.

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“…Being one of the fundamental processes required for life and survival, the metabolism of any living organism is kept running through the action and network of metabolic enzymes in a well-coordinated and tightly-regulated manner. The enzyme activity and pathway flux can be regulated through several well-known molecular and cellular processes, such as transcriptional and post-transcriptional controls [ 1 , 2 , 3 ], protein homeostatic turnover (balance between synthesis and degradation) [ 4 , 5 ], phosphorylation and dephosphorylation [ 2 , 6 ], and sequestration or translocation to different subcellular compartments [ 7 , 8 , 9 ]. Interestingly, attention is currently being focused on metabolic regulation via the supramolecular assembly or high-order structure formation of metabolic enzymes into micron-sized structures within living cells, as has been revealed in several species [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of A6E Mutation on Protein Expression and Supramolecular Assembly of Yeast Asparagine Synthetase

Surasiang

Noree

2021

Biology

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Asparagine synthetase deficiency (ASD) has been found to be caused by certain mutations in the gene encoding human asparagine synthetase (ASNS). Among reported mutations, A6E mutation showed the greatest reduction in ASNS abundance. However, the effect of A6E mutation has not yet been tested with yeast asparagine synthetase (Asn1/2p). Here, we constructed a yeast strain by deleting ASN2 from its genome, introducing the A6E mutation codon to ASN1, along with GFP downstream of ASN1. Our mutant yeast construct showed a noticeable decrease of Asn1p(A6E)-GFP levels as compared to the control yeast expressing Asn1p(WT)-GFP. At the stationary phase, the A6E mutation also markedly lowered the assembly frequency of the enzyme. In contrast to Asn1p(WT)-GFP, Asn1p(A6E)-GFP was insensitive to changes in the intracellular energy levels upon treatment with sodium azide during the log phase or fresh glucose at the stationary phase. Our study has confirmed that the effect of A6E mutation on protein expression levels of asparagine synthetase is common in both unicellular and multicellular eukaryotes, suggesting that yeast could be a model of ASD. Furthermore, A6E mutation could be introduced to the ASNS gene of acute lymphoblastic leukemia patients to inhibit the upregulation of ASNS by cancer cells, reducing the risk of developing resistance to the asparaginase treatment.

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A Systematic Protein Turnover Map for Decoding Protein Degradation

Cited by 24 publications

References 36 publications

Timer-based proteomic profiling of the ubiquitin-proteasome system reveals a substrate receptor of the GID ubiquitin ligase

Timer-based proteomic profiling of the ubiquitin-proteasome system reveals a substrate receptor of the GID ubiquitin ligase

Stellate cell computational modeling predicts signal filtering in the molecular layer circuit of cerebellum

Effects of A6E Mutation on Protein Expression and Supramolecular Assembly of Yeast Asparagine Synthetase

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