Human tra2-beta1 autoregulates its protein concentration by infuencing alternative splicing of its pre-mRNA

Peter Stoilov, Rosette Dauod, Oliver Nayler, Stefan Stamm

Research output: Contribution to journalArticlepeer-review

144 Scopus citations


HTRA2-BETA1 is an SR-like protein that regulates alternative splice site selection in a concentration-dependent manner. Its proper concentration is important as several pathological states are associated with its change. We investigated the mechanism that controls the cellular HTRA2-BETA1 concentration and found it utilizes a negative feedback loop to regulate the splicing of its exon 2. TRA2-BETA1 binds to four enhancers present in exon 2, which activates its inclusion. Inclusion of exon 2 generates mRNAs that are not translated into proteins. Mutations of exon 2 enhancers demonstrate that TRA2-BETA1 binds a degenerate sequence GHVVGANR, which is found more frequently in exons than in introns. Hyperphosphorylation of TRA2-BETA1 strongly reduces its binding to RNA. Presence of the CLK2 kinase prevents the usage of exons 2 and 3, generating the htra2-beta3 mRNA. The resulting HTRA2-BETA3 protein lacks the first RS domain of HTRA2-BETA1, is expressed in several tissues and has no influence on tra2-beta splice site selection. HTRA2-BETA1 interacting proteins promote exon 2 skipping by sequestering it, which upregulates the HTRA2-BETA1 protein synthesis. We propose that the regulation of the tra2-beta pre-mRNA alternative splicing provides a robust and sensitive molecular sensor that measures the ratio between HTRA2-BETA1 and its interacting proteins.

Original languageEnglish
Pages (from-to)509-524
Number of pages16
JournalHuman Molecular Genetics
Issue number5
StatePublished - Mar 1 2004

Bibliographical note

Funding Information:
We are grateful to Dr Javier Caceres for providing the SF2/ ASF-FF/DD clone, to Professor Albrecht Bindereif for helpful discussion, to Dr Andreas Pahl for his assistance in performing the quantitative real time PCR experiments and Guiseppe Biamonti for the full length SAF-B clone. We thank Juan Valcarcel and Douglas Black for critical reading of the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft and the European Union (QLK3-CT-2002-02062).

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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