Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expression
Abstract Alternative polyadenylation results in different 3’ isoforms of messenger RNA (mRNA) transcripts. Alternative polyadenylation in the 3’ untranslated region (3’UTR) can alter RNA localization, stability and translational efficiency. The SERPINA1 mRNA has two distinct 3’ UTR isoforms, both of...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-07569-3 |
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| author | F. N. U. Jiamutai Abigail Hatfield Austin Herbert Debarati Majumdar Vijay Shankar Lela Lackey |
| author_facet | F. N. U. Jiamutai Abigail Hatfield Austin Herbert Debarati Majumdar Vijay Shankar Lela Lackey |
| author_sort | F. N. U. Jiamutai |
| collection | DOAJ |
| description | Abstract Alternative polyadenylation results in different 3’ isoforms of messenger RNA (mRNA) transcripts. Alternative polyadenylation in the 3’ untranslated region (3’UTR) can alter RNA localization, stability and translational efficiency. The SERPINA1 mRNA has two distinct 3’ UTR isoforms, both of which express the protease inhibitor α-1-antitrypsin (A1AT). A1AT is an acute phase protein that is expressed and secreted from liver hepatocytes and upregulated during inflammation. Low levels of A1AT in the lung contributes to chronic obstructive pulmonary disease, while misfolding of A1AT in the liver contributes to liver cirrhosis. We analyzed the dynamics of alternative polyadenylation during cellular stress by treating the liver cell line HepG2 with the cytokine interleukin 6 (IL-6), ethanol or peroxide. SERPINA1 is transcriptionally upregulated after IL-6 treatment and has altered polyadenylation, resulting in an increase in long 3’UTR isoforms. We find that the long 3’UTR represses endogenous A1AT protein expression even with high levels of SERPINA1 mRNA. SERPINA1 expression and 3’ end processing are not affected by ethanol or peroxide. IL-6-induced changes in transcriptome-wide transcriptional regulation suggest changes to the endoplasmic reticulum and in secretory protein processing. Our data shows that inflammation influences polyA site choice for SERPINA1 transcripts, resulting in reduced A1AT protein expression. |
| format | Article |
| id | doaj-art-337f9b6c503d46d2a7e70ebf5bc62e1f |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-337f9b6c503d46d2a7e70ebf5bc62e1f2025-08-20T03:03:32ZengNature PortfolioScientific Reports2045-23222025-07-0115111410.1038/s41598-025-07569-3Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expressionF. N. U. Jiamutai0Abigail Hatfield1Austin Herbert2Debarati Majumdar3Vijay Shankar4Lela Lackey5Department of Genetics and Biochemistry, Center for Human Genetics, Clemson UniversityDepartment of Genetics and Biochemistry, Center for Human Genetics, Clemson UniversityDepartment of Genetics and Biochemistry, Center for Human Genetics, Clemson UniversityDepartment of Genetics and Biochemistry, Center for Human Genetics, Clemson UniversityDepartment of Genetics and Biochemistry, Center for Human Genetics, Clemson UniversityDepartment of Genetics and Biochemistry, Center for Human Genetics, Clemson UniversityAbstract Alternative polyadenylation results in different 3’ isoforms of messenger RNA (mRNA) transcripts. Alternative polyadenylation in the 3’ untranslated region (3’UTR) can alter RNA localization, stability and translational efficiency. The SERPINA1 mRNA has two distinct 3’ UTR isoforms, both of which express the protease inhibitor α-1-antitrypsin (A1AT). A1AT is an acute phase protein that is expressed and secreted from liver hepatocytes and upregulated during inflammation. Low levels of A1AT in the lung contributes to chronic obstructive pulmonary disease, while misfolding of A1AT in the liver contributes to liver cirrhosis. We analyzed the dynamics of alternative polyadenylation during cellular stress by treating the liver cell line HepG2 with the cytokine interleukin 6 (IL-6), ethanol or peroxide. SERPINA1 is transcriptionally upregulated after IL-6 treatment and has altered polyadenylation, resulting in an increase in long 3’UTR isoforms. We find that the long 3’UTR represses endogenous A1AT protein expression even with high levels of SERPINA1 mRNA. SERPINA1 expression and 3’ end processing are not affected by ethanol or peroxide. IL-6-induced changes in transcriptome-wide transcriptional regulation suggest changes to the endoplasmic reticulum and in secretory protein processing. Our data shows that inflammation influences polyA site choice for SERPINA1 transcripts, resulting in reduced A1AT protein expression.https://doi.org/10.1038/s41598-025-07569-3PolyadenylationRNA processingInterleukin 6 (IL-6)CirrhosisSERPINA1Alpha1 anti-trypsin (A1AT) |
| spellingShingle | F. N. U. Jiamutai Abigail Hatfield Austin Herbert Debarati Majumdar Vijay Shankar Lela Lackey Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expression Scientific Reports Polyadenylation RNA processing Interleukin 6 (IL-6) Cirrhosis SERPINA1 Alpha1 anti-trypsin (A1AT) |
| title | Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expression |
| title_full | Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expression |
| title_fullStr | Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expression |
| title_full_unstemmed | Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expression |
| title_short | Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expression |
| title_sort | altered polyadenylation site usage in serpina1 3 utr in response to cellular stress affects a1at protein expression |
| topic | Polyadenylation RNA processing Interleukin 6 (IL-6) Cirrhosis SERPINA1 Alpha1 anti-trypsin (A1AT) |
| url | https://doi.org/10.1038/s41598-025-07569-3 |
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