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The microbial valorization of lignin is challenging due to the toxicity of its degradation intermediates, particularly formaldehyde. In this study, we engineered\n                      <jats:italic toggle=\"yes\">Methylobacterium extorquens<\/jats:italic>\n                      PA1 to metabolize lignin-derived methoxylated aromatics, vanillate (VA) and protocatechuate (PCA), by introducing the\n                      <jats:italic toggle=\"yes\">van<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">pca<\/jats:italic>\n                      gene clusters. Compared to\n                      <jats:italic toggle=\"yes\">Pseudomonas putida<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">M. extorquens<\/jats:italic>\n                      PA1 exhibited better formaldehyde detoxification, enabling robust growth on VA without accumulation of formaldehyde. Genetic analyses confirmed that formaldehyde oxidation and stress response systems, rather than C\n                      <jats:sub>1<\/jats:sub>\n                      assimilation, were important for VA metabolism. Additionally, VA and PCA were found to disrupt membrane potential, contributing to their inherent toxicity. Our findings establish\n                      <jats:italic toggle=\"yes\">M. extorquens<\/jats:italic>\n                      PA1 as a promising chassis for lignin valorization and provide a framework for engineering formaldehyde-resistant microbial platforms.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        In developing biotechnological solutions for a circular economy, it is critical to valorize all parts of renewable resources, such as lignocellulose from vegetative components of agricultural crops and from bioenergy feedstocks. After chemical breakdown, the aromatics arising from lignin present significant challenges for use due to their toxicity. Here, we address one component of this challenge\u2014the methoxy groups that get released as formaldehyde\u2014and show that existing biotechnological platform organisms with strong formaldehyde metabolism, such as\n                        <jats:italic toggle=\"yes\">Methylobacterium extorquens<\/jats:italic>\n                        , can be transformed into highly capable utilizers of methoxylated aromatics.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/msphere.00171-25","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T10:40:51Z","timestamp":1753958451000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Engineered\n                    <i>Methylobacterium extorquens<\/i>\n                    grows well on methoxylated aromatics due to its formaldehyde metabolism and stress response"],"prefix":"10.1128","volume":"10","author":[{"given":"Akorede L.","family":"Seriki","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Idaho","place":["Moscow, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3589-6914","authenticated-orcid":true,"given":"Alexander B.","family":"Alleman","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Idaho","place":["Moscow, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomislav","family":"Ticak","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Idaho","place":["Moscow, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa C.","family":"Baugh","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Idaho","place":["Moscow, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack W.","family":"Creagh","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Idaho","place":["Moscow, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5189-4580","authenticated-orcid":true,"given":"Christopher J.","family":"Marx","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Idaho","place":["Moscow, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/polym15153177"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.progpolymsci.2013.11.004"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-004-1642-2"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.00289-17"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5GC03061G"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1104\/pp.110.155119"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.3390\/biomass2030009"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.4061\/2011\/787532"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/cssc.201402503"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8137.2010.03327.x"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1023\/B:PHYT.0000047809.65444.a4"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241411668"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1080\/26395940.2023.2263168"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","unstructured":"Wolf ME Lalande AT Newman BL Bleem AC Palumbo CT Beckham GT Eltis LD. 2024. 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