Regulated protein degradation underlies the timely execution of essential gene expression programs in bacteria. Here, we deployed time-resolved chemoproteomics, text mining of the PubMed and EcoCyc knowledge bases, and machine learning classification to identify proteolytic regulation in exponential and stationary phase Escherichia coli cultures. We experimentally validated the instability of diverse homeostatic and stress response regulators, including the principal cyclic-di-GMP phosphodiesterase PdeH, the N-end rule substrate chaperone ClpS, and all four A-type domain iron–sulfur cluster carriers, IscA, ErpA, NfuA, and SufA. Mutagenesis of the PdeH N-terminal extension abolished ClpXP recognition, thereby impairing stationary phase depletion of PdeH and altering macrocolony biofilm surface morphology. Unstable proteins synthesized in stationary phase such as the morphology regulator BolA, RNA polymerase ω subunit, and the biofilm regulator BssR were implicated in quiescence. Finally, machine learning–assisted substrate identification revealed Lon-mediated degradation of two opposing key regulators of surface adhesion, the RpoS antagonist FliZ and the major biofilm regulator CsgD, suggesting proteolysis may hasten transitions between motility and sessility. Together, these results highlight the role of regulated proteolysis in driving physiological adaptation for this model organism.
", "doi": "10.1073/pnas.2515265123", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences", "publication_date": "2026-03-10", "series_number": "10", "volume": "123", "issue": "10", "pages": "e2515265123" }, { "id": "authors:jhh97-h1c30", "collection": "authors", "collection_id": "jhh97-h1c30", "cite_using_url": "https://authors.library.caltech.edu/records/jhh97-h1c30", "type": "article", "title": "The gut microbiome promotes mitochondrial respiration in the brain of a Parkinson's disease mouse model", "author": [ { "family_name": "Morais", "given_name": "Livia H.", "orcid": "0000-0002-5738-2658", "clpid": "Morais-Livia-H" }, { "family_name": "Stiles", "given_name": "Linsey" }, { "family_name": "Freeman", "given_name": "Milla", "clpid": "Freeman-Milla" }, { "family_name": "Oguienko", "given_name": "Anastasiya D.", "orcid": "0000-0002-8473-6378", "clpid": "Oguienko-Anastasiya-D" }, { "family_name": "Hoang", "given_name": "Jonathan D.", "orcid": "0000-0002-3762-9596", "clpid": "Hoang-Jonathan-D" }, { "family_name": "Ji", "given_name": "Jenny", "orcid": "0000-0002-7901-5605", "clpid": "Ji-Jenny" }, { "family_name": "Jones", "given_name": "Jeff", "orcid": "0000-0002-7142-2222", "clpid": "Jones-Jeff" }, { "family_name": "Quan", "given_name": "Baiyi", "orcid": "0000-0001-6313-4274", "clpid": "Quan-Baiyi" }, { "family_name": "Devine", "given_name": "Jack", "clpid": "Devine-Jack" }, { "family_name": "Bois", "given_name": "Justin S.", "orcid": "0000-0001-7137-8746", "clpid": "Bois-J-S" }, { "family_name": "Chou", "given_name": "Tsui-Fen", "orcid": "0000-0003-2410-2186", "clpid": "Chou-Tsui-Fen" }, { "family_name": "Trinh", "given_name": "Joanne" }, { "family_name": "Picard", "given_name": "Martin" }, { "family_name": "Gradinaru", "given_name": "Viviana", "orcid": "0000-0001-5868-348X", "clpid": "Gradinaru-V" }, { "family_name": "Mazmanian", "given_name": "Sarkis K.", "orcid": "0000-0003-2713-1513", "clpid": "Mazmanian-S-K" } ], "abstract": "The pathophysiology of Parkinson’s disease (PD) involves gene-environment interactions that impair various cellular processes including mitochondrial dysfunction. Mitochondria-associated mutations increase PD risk, respiration is altered in the PD brain, and mitochondria-damaging toxicants cause PD-like motor and gastrointestinal symptoms in animal models. The gut microbiome is altered in PD, representing an environmental risk, however a relationship between mitochondrial function and the microbiome in PD has not been previously established. Herein, we discover that dysregulation of mitochondria-associated genes and hyperactive striatal mitochondria are induced by the microbiome in α-synuclein-overexpressing (Thy1-ASO) mice. Thy1-ASO mice elaborate increased reactive oxygen species in the striatum whereas germ-free counterparts express increased oxygen scavenging proteins. Indeed, treatment with an antioxidant drug improves motor performance in Thy1-ASO mice and blocking oxidant scavenging in germ-free mice enhances motor deficits in an α-synuclein dependent manner. Thus, the gut microbiome promotes motor symptoms in a mouse model of PD via increased mitochondrial respiration and oxidative stress in the brain.
", "doi": "10.1038/s41531-025-01142-5", "pmcid": "PMC12537952", "issn": "2373-8057", "publisher": "Nature Publishing Group", "publication": "npj Parkinson's Disease", "publication_date": "2025-10-20", "volume": "11", "pages": "301" }, { "id": "authors:ryb4b-15p31", "collection": "authors", "collection_id": "ryb4b-15p31", "cite_using_url": "https://authors.library.caltech.edu/records/ryb4b-15p31", "type": "article", "title": "Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer", "author": [ { "family_name": "Mohanty", "given_name": "Atish", "orcid": "0000-0003-1464-3165", "clpid": "Mohanty-Atish" }, { "family_name": "Nam", "given_name": "Arin" }, { "family_name": "Srivastava", "given_name": "Saumya" }, { "family_name": "Jones", "given_name": "Jeff", "orcid": "0000-0002-7142-2222", "clpid": "Jones-Jeff" }, { "family_name": "Lomenick", "given_name": "Brett", "orcid": "0000-0002-5023-9998", "clpid": "Lomenick-Brett" }, { "family_name": "Singhal", "given_name": "Sharad S.", "orcid": "0000-0002-6415-8160" }, { "family_name": "Guo", "given_name": "Linlin" }, { "family_name": "Cho", "given_name": "Hyejin", "orcid": "0000-0002-9954-8118" }, { "family_name": "Li", "given_name": "Aimin" }, { "family_name": "Behal", "given_name": "Amita" }, { "family_name": "Mirzapoiazova", "given_name": "Tamara", "orcid": "0000-0001-9353-229X" }, { "family_name": "Massarelli", "given_name": "Erminia", "orcid": "0000-0001-7798-7286" }, { "family_name": "Koczywas", "given_name": "Marianna", "orcid": "0000-0002-1588-6292" }, { "family_name": "Arvanitis", "given_name": "Leonidas D.", "orcid": "0000-0002-4744-8350" }, { "family_name": "Walser", "given_name": "Tonya", "orcid": "0000-0002-3319-4361" }, { "family_name": "Villaflor", "given_name": "Victoria", "orcid": "0000-0002-9111-1034" }, { "family_name": "Hamilton", "given_name": "Stanley", "orcid": "0000-0002-8331-1052" }, { "family_name": "Mambetsariev", "given_name": "Isa", "orcid": "0000-0003-2882-0249" }, { "family_name": "Sattler", "given_name": "Martin", "orcid": "0000-0001-5053-4199" }, { "family_name": "Nasser", "given_name": "Mohd W.", "orcid": "0000-0003-2070-4972" }, { "family_name": "Jain", "given_name": "Maneesh", "orcid": "0000-0002-2020-3687" }, { "family_name": "Batra", "given_name": "Surinder K.", "orcid": "0000-0001-9470-9317" }, { "family_name": "Soldi", "given_name": "Raffaella", "orcid": "0000-0002-2176-3694" }, { "family_name": "Sharma", "given_name": "Sunil" }, { "family_name": "Fakih", "given_name": "Marwan", "orcid": "0000-0002-6554-5488" }, { "family_name": "Mohanty", "given_name": "Saswat Kumar", "orcid": "0000-0002-1813-589X" }, { "family_name": "Mainan", "given_name": "Avijit", "orcid": "0000-0002-1264-3674" }, { "family_name": "Wu", "given_name": "Xiwei", "orcid": "0000-0002-7071-1671" }, { "family_name": "Chen", "given_name": "Yihong" }, { "family_name": "He", "given_name": "Yanan" }, { "family_name": "Chou", "given_name": "Tsui-Fen", "orcid": "0000-0003-2410-2186", "clpid": "Chou-Tsui-Fen" }, { "family_name": "Roy", "given_name": "Susmita", "orcid": "0000-0001-6411-4347" }, { "family_name": "Orban", "given_name": "John", "orcid": "0000-0002-3895-1800" }, { "family_name": "Kulkarni", "given_name": "Prakash" }, { "family_name": "Salgia", "given_name": "Ravi", "orcid": "0000-0001-9643-7626" } ], "abstract": "Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that acquired resistance to sotorasib in isogenic cells correlated with increased expression of integrin \u03b24 (ITGB4), a component of the focal adhesion complex. Silencing ITGB4 in tolerant cells improved sotorasib sensitivity, while overexpressing ITGB4 enhanced tolerance to sotorasib by supporting AKT-mTOR bypass signaling. Chronic treatment with sotorasib induced WNT expression and activated the WNT/\u03b2-catenin signaling pathway. Thus, silencing both ITGB4 and \u03b2-catenin significantly improved sotorasib sensitivity in tolerant, acquired, and inherently resistant cells. In addition, the proteasome inhibitor carfilzomib (CFZ) exhibited synergism with sotorasib by down-regulating ITGB4 and \u03b2-catenin expression. Furthermore, adagrasib phenocopies the combination effect of sotorasib and CFZ by suppressing KRAS activity and inhibiting cell cycle progression in inherently resistant cells. Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying resistance to sotorasib and propose a promising treatment strategy to overcome resistance.", "doi": "10.1126/sciadv.ade3816", "pmcid": "PMC10575592", "issn": "2375-2548", "publisher": "American Association for the Advancement of Science", "publication": "Science Advances", "publication_date": "2023-10-13", "series_number": "41", "volume": "9", "issue": "41", "pages": "eade3816" }, { "id": "authors:w8tyx-7qq38", "collection": "authors", "collection_id": "w8tyx-7qq38", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220603-698843600", "type": "article", "title": "Surface cysteines could protect the SARS-CoV-2 main protease from oxidative damage", "author": [ { "family_name": "Ravanfar", "given_name": "Raheleh", "orcid": "0000-0003-2992-0575", "clpid": "Ravanfar-Raheleh" }, { "family_name": "Sheng", "given_name": "Yuling", "clpid": "Sheng-Yuling" }, { "family_name": "Shahgholi", "given_name": "Mona", "orcid": "0000-0002-8879-4305", "clpid": "Shahgholi-Mona" }, { "family_name": "Lomenick", "given_name": "Brett", "orcid": "0000-0002-5023-9998", "clpid": "Lomenick-Brett" }, { "family_name": "Jones", "given_name": "Jeff", "clpid": "Jones-Jeff" }, { "family_name": "Chou", "given_name": "Tsui-Fen", "orcid": "0000-0003-2410-2186", "clpid": "Chou-Tsui-Fen" }, { "family_name": "Gray", "given_name": "Harry B.", "orcid": "0000-0002-7937-7876", "clpid": "Gray-H-B" }, { "family_name": "Winkler", "given_name": "Jay R.", "orcid": "0000-0002-4453-9716", "clpid": "Winkler-Jay-R" } ], "abstract": "The SARS-CoV-2 main protease (M\u1d56\u02b3\u1d52) is responsible for cleaving twelve nonstructural proteins from the viral polyprotein. M\u1d56\u02b3\u1d52, a cysteine protease, is characterized by a large number of noncatalytic cysteine (Cys) residues, none involved in disulfide bonds. In the absence of a tertiary-structure stabilizing role for these residues, a possible alternative is that they are involved in redox processes. We report experimental work in support of a proposal that surface cysteines on M^(pro) can protect the active-site Cys145 from oxidation by reactive oxygen species (ROS). In investigations of enzyme kinetics, we found that mutating three surface cysteines to serines did not greatly affect activity, which in turn indicates that these cysteines could protect Cys145 from oxidative damage.", "doi": "10.1016/j.jinorgbio.2022.111886", "pmcid": "PMC9161685", "issn": "0162-0134", "publisher": "Elsevier", "publication": "Journal of Inorganic Biochemistry", "publication_date": "2022-09", "volume": "234", "pages": "Art. No. 111886" } ]