Reduction in adaptor amounts establishes degradation hierarchy among protease substrates

Yeom, Jinki; Gao, Xiaohui; Groisman, Eduardo A.

doi:10.1073/pnas.1722246115

Cited by 16 publications

(33 citation statements)

References 65 publications

(94 reference statements)

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“…The Qad-dependent acetylation of the HspQ protein is predicted to alter the abundance of a significant portion of the Salmonella proteome by narrowing the substrate spectrum of the ClpSAP and Lon proteases. This is because the substrates of Lon (Takaya et al 2005;Madrid et al 2007) and ClpSAP (Yeom et al 2018) include several regulatory DNA-binding proteins as well as enzymes that alter the abundance of key metabolites such as polyamines.…”

Section: Discussionmentioning

confidence: 99%

“…S6A). In contrast, the abundance of the control ClpS-dependent ClpAP substrate Oat (Yeom et al 2018) was higher in the clpS mutant than in wild-type Salmonella (Supplemental Fig. S6B,C) and lower in the hspQ and qad single mutants than in the wild-type strain ( Supplemental Fig.…”

Section: The In Vivo Abundance Of Clps-independent Clpap Substrates Imentioning

confidence: 99%

“…To construct strains specifying a C-terminally Flag-tagged HspQ protein (JY674, JY692, JY695, and JY740), a cat cassette was introduced at the 3 ′ end of hspQ: A cat gene fragment was amplified from pKD3 using primers 16044/16045 for hspQ-Flag and then introduced into wild-type Salmonella 14028s, clpS-HA (JY691) (Yeom et al 2018), clpA-HA (JY694) (Yeom et al 2018), and qad::kan (JY889) strains, each harboring plasmid pKD46. The resulting strains was kept at 30°C and transformed with pCP20 to remove the cat cassette.…”

Section: Construction Of Chromosomal Mutants and Plasmidsmentioning

confidence: 99%

“…Strains JY686, JY687, JY699, JY700, JY873, and JY875 were made by transducing the hspQ::cat insertion into strains JY655 (Yeom et al 2018), JY657 (Yeom et al 2018), JY694 (Yeom et al 2018), JY691 (Yeom et al 2018), JY872, and JY874, respectively, using a P22 lysate generated in strain JY683.…”

Section: Construction Of Chromosomal Mutants and Plasmidsmentioning

confidence: 99%

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Activator of one protease transforms into inhibitor of another in response to nutritional signals

Yeom

Groisman

2019

Genes Dev.

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All cells use proteases to adjust protein amounts. Proteases maintain protein homeostasis by degrading nonfunctional toxic proteins and play regulatory roles by targeting particular substrates in response to specific signals. Here we address how cells tune protease specificity to nutritional signals. We report that Salmonella enterica increases the specificity of the broadly conserved proteases Lon and ClpSAP by transforming the Lon activator and substrate HspQ into an inhibitor of the N-degron recognin ClpS, the adaptor of the ClpAP protease. We establish that upon acetylation, HspQ stops being a Lon activator and substrate and that the accumulated HspQ binds to ClpS, hindering degradation of ClpSAP substrates. Growth on glucose promotes HspQ acetylation by increasing acetyl-CoA amounts, thereby linking metabolism to proteolysis. By altering protease specificities but continuing to degrade junk proteins, cells modify the abundance of particular proteins while preserving the quality of their proteomes. This rapid response mechanism linking protease specificity to nutritional signals is broadly conserved.

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Section: Discussionmentioning

confidence: 99%

Section: The In Vivo Abundance Of Clps-independent Clpap Substrates Imentioning

confidence: 99%

Section: Construction Of Chromosomal Mutants and Plasmidsmentioning

confidence: 99%

Section: Construction Of Chromosomal Mutants and Plasmidsmentioning

confidence: 99%

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Activator of one protease transforms into inhibitor of another in response to nutritional signals

Yeom

Groisman

2019

Genes Dev.

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“…1D), but also N-terminus-proximal internal degrons in bacterial proteins, such as PhoP (ref. 54 and references therein). In a pathway that regulates PhoP, the MgtC protein competes with ClpS for the binding to PhoP, and thereby protects PhoP from degradation.…”

Section: The Bacterial Leu/n-degron Pathwaymentioning

confidence: 99%

N-degron and C-degron pathways of protein degradation

Varshavsky

2019

Proc. Natl. Acad. Sci. U.S.A.

402

501

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This perspective is partly review and partly proposal. N-degrons and C-degrons are degradation signals whose main determinants are, respectively, the N-terminal and C-terminal residues of cellular proteins. Ndegrons and C-degrons include, to varying extents, adjoining sequence motifs, and also internal lysine residues that function as polyubiquitylation sites. Discovered in 1986, N-degrons were the first degradation signals in short-lived proteins. A particularly large set of C-degrons was discovered in 2018. We describe multifunctional proteolytic systems that target N-degrons and C-degrons. We also propose to denote these systems as "N-degron pathways" and "C-degron pathways." The former notation replaces the earlier name "N-end rule pathways." The term "N-end rule" was introduced 33 years ago, when only some N-terminal residues were thought to be destabilizing. However, studies over the last three decades have shown that all 20 amino acids of the genetic code can act, in cognate sequence contexts, as destabilizing N-terminal residues. Advantages of the proposed terms include their brevity and semantic uniformity for N-degrons and C-degrons. In addition to being topologically analogous, N-degrons and C-degrons are related functionally. A proteolytic cleavage of a subunit in a multisubunit complex can create, at the same time, an Ndegron (in a C-terminal fragment) and a spatially adjacent C-degron (in an N-terminal fragment). Consequently, both fragments of a subunit can be selectively destroyed through attacks by the N-degron and C-degron pathways.The lifespans of protein molecules in a cell range from less than a minute to many days. Regulated protein degradation protects cells from misfolded, aggregated, or otherwise abnormal proteins, and also controls the levels of proteins that evolved to be short-lived in vivo. Some proteolytic pathways can selectively destroy a specific subunit of a protein complex. Such pathways can act as proteinremodeling devices (1). They can either activate or inactivate a protein machine, change its enzymatic specificity, alter its subunit composition, or repair an oligomeric complex, for example, by destroying fragments of a cleaved subunit that are still embedded in the complex. This would allow a replacement of the cleaved subunit by its intact counterpart. Many biological transitions involve remodeling of protein complexes through subunit-selective degradation, in settings that range from cell-division cycles and circadian circuits to cell differentiation and responses to stresses.One function of protein degradation is the quality control of nascent and newly formed proteins. Selective proteolysis eliminates those proteins (including mutant ones) that fold too slowly, misfold, or do not satisfy other requirements of quality control. Most proteins function as multisubunit complexes, which often assemble cotranslationally. Quality-control systems destroy subunits that are either overproduced relative to other subunits of a complex or do not become incorporated into a complex rapi...

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Expression and function of clpS and clpA in Xanthomonas campestris pv. campestris

Chang

Liao

et al. 2022

Antonie van Leeuwenhoek

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ATP-dependent proteases (FtsH, Lon, and Clp family proteins) are ubiquitous in bacteria and play essential roles in many regulatory cell processes. Xanthomonas campestris pv. campestris is a Gramnegative pathogen and can cause black rot diseases in crucifers. The genome of X. campestris pv. campestris have several clp genes, namely clpS, clpA, clpX, clpP, clpQ, and clpY. Among them, only clpX and clpP were known to be required for pathogenicity. Here, we focused on two uncharacterized clp genes (clpS and clpA) that encode the adaptor (ClpS) and ATPase subunit (ClpA) of the ClpAP protease complex, respectively. Transcriptional analysis revealed that expression of both clpS and clpA is induced by heat shock. Inactivation of clpA but not clpS resulted in susceptibility to high temperature and revealed an attenuation of virulence on the host plant. The altered phenotypes of the clpA mutant could be complemented in trans. Site-directed mutagenesis revealed that K223 and K504 are critical amino acid residues for ClpA function in heat tolerance. The clpA mutant revealed different protein expression pro les as compared to the wild type in response to heat stress. Taken together, we characterized two clp genes (clpS and clpA) by examining their expression and function including stress tolerance and pathogenicity. We demonstrated that both clpS and clpA are expressed in a temperature dependent manner, and clpA is required for survival at high temperature and full virulence of X. campestris pv. campestris. This is the rst time that clpS and clpA has been characterized in Xanthomonas.

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Reduction in adaptor amounts establishes degradation hierarchy among protease substrates

Cited by 16 publications

References 65 publications

Activator of one protease transforms into inhibitor of another in response to nutritional signals

Activator of one protease transforms into inhibitor of another in response to nutritional signals

N-degron and C-degron pathways of protein degradation

Expression and function of clpS and clpA in Xanthomonas campestris pv. campestris

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