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By periodically switching the expressed VSG antigen, parasites evade host immune responses.\n                    <jats:italic>VSG<\/jats:italic>\n                    mRNA constitutes ~10% of total cellular mRNA, and depletion of\n                    <jats:italic>VSG<\/jats:italic>\n                    transcripts is lethal. When two VSGs are expressed simultaneously, however, total\n                    <jats:italic>VSG<\/jats:italic>\n                    mRNA levels remain close to wild-type amounts, indicating the presence of a balancing mechanism that limits the overall abundance of these highly expressed transcripts. Using inducible and constitutive expression systems, we found that attenuation of endogenous\n                    <jats:italic>VSG<\/jats:italic>\n                    mRNA requires efficient engagement of ectopic transcripts with the endoplasmic reticulum (ER). This response occurs independently of efficient VSG protein production and does not require a\n                    <jats:italic>VSG<\/jats:italic>\n                    open reading frame. In contrast, abundant transcripts lacking functional ER-engagement signals fail to trigger balancing despite containing the\n                    <jats:italic>VSG<\/jats:italic>\n                    3\u2032 UTR 16-mer stability element. These results indicate that the signal for\n                    <jats:italic>VSG<\/jats:italic>\n                    mRNA regulation is the presence of abundant ER-engaged transcripts (i.e., transcripts undergoing co-translational targeting to the ER), rather than VSG-specific sequence features or productive protein synthesis. Based on our findings together with previous work, we propose an ER-engagement-coupled homeostatic attenuation mechanism in which increased ER-engaged transcript load elicits a regulatory response that reduces endogenous\n                    <jats:italic>VSG<\/jats:italic>\n                    mRNA abundance. This model links the cytoplasmic burden of ER-targeted transcripts to transcriptional control of the nuclear VSG expression site, providing a mechanism that could allow trypanosomes to couple secretory pathway capacity to surface antigen expression. Such a mechanism could enable trypanosomes to maintain secretory pathway homeostasis while supporting rapid surface-coat remodelling during antigenic variation.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014518","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:41:03Z","timestamp":1787074863000},"page":"e1014518","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endoplasmic reticulum engagement of transcripts triggers VSG mRNA balancing in trypanosomes"],"prefix":"10.1371","volume":"22","author":[{"given":"Erick O.","family":"Aroko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Meyer-Natus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Batram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Wei\u00dfenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Henning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majeed","family":"Bakari-Soale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola G.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1436-5759","authenticated-orcid":true,"given":"Markus","family":"Engstler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"issue":"3","key":"ppat.1014518.ref001","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.cell.2007.08.046","article-title":"Hydrodynamic flow-mediated protein sorting on the cell surface of trypanosomes","volume":"131","author":"M Engstler","year":"2007","journal-title":"Cell"},{"issue":"6229","key":"ppat.1014518.ref002","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1126\/science.aaa4502","article-title":"The in vivo dynamics of antigenic variation in Trypanosoma brucei","volume":"347","author":"MR Mugnier","year":"2015","journal-title":"Science"},{"issue":"4","key":"ppat.1014518.ref003","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.mib.2004.05.001","article-title":"Antigenic variation in Trypanosoma brucei: facts, challenges and mysteries","volume":"7","author":"E Pays","year":"2004","journal-title":"Curr Opin Microbiol"},{"key":"ppat.1014518.ref004","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1146\/annurev.bi.50.070181.001533","article-title":"Transfer of proteins across membranes","volume":"50","author":"G Kreil","year":"1981","journal-title":"Annu Rev Biochem"},{"key":"ppat.1014518.ref005","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/0166-6851(81)90021-9","article-title":"Biosynthesis of Trypanosoma brucei variant surface glycoprotein. 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