Tristetraprolin inhibits poly(A)-tail synthesis in nuclear mRNA that contains AU-rich elements by interacting with poly(A)-binding protein nuclear 1.
BACKGROUND: Tristetraprolin binds mRNA AU-rich elements and thereby facilitates the destabilization of mature mRNA in the cytosol. METHODOLOGY/PRINCIPAL FINDINGS: To understand how tristetraprolin mechanistically functions, we biopanned with a phage-display library for proteins that interact with tr...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3406032?pdf=render |
| _version_ | 1819041844172947456 |
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| author | Yu-Lun Su Shun-Chang Wang Pei-Yu Chiang Nien-Yi Lin Yu-Fang Shen Geen-Dong Chang Ching-Jin Chang |
| author_facet | Yu-Lun Su Shun-Chang Wang Pei-Yu Chiang Nien-Yi Lin Yu-Fang Shen Geen-Dong Chang Ching-Jin Chang |
| author_sort | Yu-Lun Su |
| collection | DOAJ |
| description | BACKGROUND: Tristetraprolin binds mRNA AU-rich elements and thereby facilitates the destabilization of mature mRNA in the cytosol. METHODOLOGY/PRINCIPAL FINDINGS: To understand how tristetraprolin mechanistically functions, we biopanned with a phage-display library for proteins that interact with tristetraprolin and retrieved, among others, a fragment of poly(A)-binding protein nuclear 1, which assists in the 3'-polyadenylation of mRNA by binding to immature poly(A) tails and thereby increases the activity of poly(A) polymerase, which is directly responsible for polyadenylation. The tristetraprolin/poly(A)-binding protein nuclear 1 interaction was characterized using tristetraprolin and poly(A)-binding protein nuclear 1 deletion mutants in pull-down and co-immunoprecipitation assays. Tristetraprolin interacted with the carboxyl-terminal region of poly(A)-binding protein nuclear 1 via its tandem zinc finger domain and another region. Although tristetraprolin and poly(A)-binding protein nuclear 1 are located in both the cytoplasm and the nucleus, they interacted in vivo in only the nucleus. In vitro, tristetraprolin bound both poly(A)-binding protein nuclear 1 and poly(A) polymerase and thereby inhibited polyadenylation of AU-rich element-containing mRNAs encoding tumor necrosis factor α, GM-CSF, and interleukin-10. A tandem zinc finger domain-deleted tristetraprolin mutant was a less effective inhibitor. Expression of a tristetraprolin mutant restricted to the nucleus resulted in downregulation of an AU-rich element-containing tumor necrosis factor α/luciferase mRNA construct. CONCLUSION/SIGNIFICANCE: In addition to its known cytosolic mRNA-degrading function, tristetraprolin inhibits poly(A) tail synthesis by interacting with poly(A)-binding protein nuclear 1 in the nucleus to regulate expression of AU-rich element-containing mRNA. |
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| format | Article |
| id | doaj.art-3ce40d32975c479684157f240bbe377f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T09:31:27Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3ce40d32975c479684157f240bbe377f2022-12-21T19:08:44ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0177e4131310.1371/journal.pone.0041313Tristetraprolin inhibits poly(A)-tail synthesis in nuclear mRNA that contains AU-rich elements by interacting with poly(A)-binding protein nuclear 1.Yu-Lun SuShun-Chang WangPei-Yu ChiangNien-Yi LinYu-Fang ShenGeen-Dong ChangChing-Jin ChangBACKGROUND: Tristetraprolin binds mRNA AU-rich elements and thereby facilitates the destabilization of mature mRNA in the cytosol. METHODOLOGY/PRINCIPAL FINDINGS: To understand how tristetraprolin mechanistically functions, we biopanned with a phage-display library for proteins that interact with tristetraprolin and retrieved, among others, a fragment of poly(A)-binding protein nuclear 1, which assists in the 3'-polyadenylation of mRNA by binding to immature poly(A) tails and thereby increases the activity of poly(A) polymerase, which is directly responsible for polyadenylation. The tristetraprolin/poly(A)-binding protein nuclear 1 interaction was characterized using tristetraprolin and poly(A)-binding protein nuclear 1 deletion mutants in pull-down and co-immunoprecipitation assays. Tristetraprolin interacted with the carboxyl-terminal region of poly(A)-binding protein nuclear 1 via its tandem zinc finger domain and another region. Although tristetraprolin and poly(A)-binding protein nuclear 1 are located in both the cytoplasm and the nucleus, they interacted in vivo in only the nucleus. In vitro, tristetraprolin bound both poly(A)-binding protein nuclear 1 and poly(A) polymerase and thereby inhibited polyadenylation of AU-rich element-containing mRNAs encoding tumor necrosis factor α, GM-CSF, and interleukin-10. A tandem zinc finger domain-deleted tristetraprolin mutant was a less effective inhibitor. Expression of a tristetraprolin mutant restricted to the nucleus resulted in downregulation of an AU-rich element-containing tumor necrosis factor α/luciferase mRNA construct. CONCLUSION/SIGNIFICANCE: In addition to its known cytosolic mRNA-degrading function, tristetraprolin inhibits poly(A) tail synthesis by interacting with poly(A)-binding protein nuclear 1 in the nucleus to regulate expression of AU-rich element-containing mRNA.http://europepmc.org/articles/PMC3406032?pdf=render |
| spellingShingle | Yu-Lun Su Shun-Chang Wang Pei-Yu Chiang Nien-Yi Lin Yu-Fang Shen Geen-Dong Chang Ching-Jin Chang Tristetraprolin inhibits poly(A)-tail synthesis in nuclear mRNA that contains AU-rich elements by interacting with poly(A)-binding protein nuclear 1. PLoS ONE |
| title | Tristetraprolin inhibits poly(A)-tail synthesis in nuclear mRNA that contains AU-rich elements by interacting with poly(A)-binding protein nuclear 1. |
| title_full | Tristetraprolin inhibits poly(A)-tail synthesis in nuclear mRNA that contains AU-rich elements by interacting with poly(A)-binding protein nuclear 1. |
| title_fullStr | Tristetraprolin inhibits poly(A)-tail synthesis in nuclear mRNA that contains AU-rich elements by interacting with poly(A)-binding protein nuclear 1. |
| title_full_unstemmed | Tristetraprolin inhibits poly(A)-tail synthesis in nuclear mRNA that contains AU-rich elements by interacting with poly(A)-binding protein nuclear 1. |
| title_short | Tristetraprolin inhibits poly(A)-tail synthesis in nuclear mRNA that contains AU-rich elements by interacting with poly(A)-binding protein nuclear 1. |
| title_sort | tristetraprolin inhibits poly a tail synthesis in nuclear mrna that contains au rich elements by interacting with poly a binding protein nuclear 1 |
| url | http://europepmc.org/articles/PMC3406032?pdf=render |
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