{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:12:55Z","timestamp":1772172775692,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008492","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000}}],"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T00:00:00Z","timestamp":1609113600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Protein turnover is vital to cellular homeostasis. Many proteins are degraded efficiently only after they have been post-translationally \u201ctagged\u201d with a polyubiquitin chain. Ubiquitylation is a form of Post-Translational Modification (PTM): addition of a ubiquitin to the chain is catalyzed by E3 ligases, and removal of ubiquitin is catalyzed by a De-UBiquitylating enzyme (DUB). Nearly four decades ago, Goldbeter and Koshland discovered that reversible PTM cycles function like on-off switches when the substrates are at saturating concentrations. Although this finding has had profound implications for the understanding of switch-like behavior in biochemical networks, the general behavior of PTM cycles subject to synthesis and degradation has not been studied. Using a mathematical modeling approach, we found that simply introducing protein turnover to a standard modification cycle has profound effects, including significantly reducing the switch-like nature of the response. Our findings suggest that many classic results on PTM cycles may not hold\n                    <jats:italic>in vivo<\/jats:italic>\n                    where protein turnover is ubiquitous. We also found that proteins sharing an E3 ligase can have closely related changes in their expression levels. These results imply that it may be difficult to interpret experimental results obtained from either overexpressing or knocking down protein levels, since changes in protein expression can be coupled via E3 ligase crosstalk. Understanding crosstalk and competition for E3 ligases will be key in ultimately developing a global picture of protein homeostasis.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1008492","type":"journal-article","created":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T16:12:16Z","timestamp":1609171936000},"page":"e1008492","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Crosstalk and ultrasensitivity in protein degradation pathways"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3588-5358","authenticated-orcid":true,"given":"Abhishek","family":"Mallela","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6646-2353","authenticated-orcid":true,"given":"Maulik K.","family":"Nariya","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2868-7495","authenticated-orcid":true,"given":"Eric J.","family":"Deeds","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2020,12,28]]},"reference":[{"issue":"Pt 1","key":"pcbi.1008492.ref001","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1242\/jcs.115.1.141","article-title":"The role of IKK in constitutive activation of NF-kappaB transcription factor in prostate carcinoma cells","volume":"115","author":"AV Gasparian","year":"2002","journal-title":"J Cell Sci"},{"issue":"22","key":"pcbi.1008492.ref002","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.2174\/1568026611212220014","article-title":"Protein homeostasis as a therapeutic target for diseases of protein conformation","volume":"12","author":"B Calamini","year":"2012","journal-title":"Curr Top Med Chem"},{"key":"pcbi.1008492.ref003","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1146\/annurev.biochem.052308.114844","article-title":"Biological and chemical approaches to diseases of proteostasis deficiency","volume":"78","author":"ET Powers","year":"2009","journal-title":"Annu Rev Biochem"},{"key":"pcbi.1008492.ref004","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1146\/annurev.biochem.78.081507.101607","article-title":"Recognition and processing of ubiquitin-protein conjugates by the proteasome","volume":"78","author":"D Finley","year":"2009","journal-title":"Annu Rev Biochem"},{"key":"pcbi.1008492.ref005","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1146\/annurev-biochem-060310-170328","article-title":"The ubiquitin code","volume":"81","author":"D Komander","year":"2012","journal-title":"Annu Rev Biochem"},{"issue":"11","key":"pcbi.1008492.ref006","doi-asserted-by":"crossref","first-page":"6840","DOI":"10.1073\/pnas.78.11.6840","article-title":"An amplified sensitivity arising from covalent modification in biological systems","volume":"78","author":"A Goldbeter","year":"1981","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"23","key":"pcbi.1008492.ref007","doi-asserted-by":"crossref","first-page":"14441","DOI":"10.1016\/S0021-9258(17)42619-6","article-title":"Ultrasensitivity in biochemical systems controlled by covalent modification. 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