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Human Molecular Genetics Advance Access originally published online on January 6, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 5 509-524
DOI: 10.1093/hmg/ddh051

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

Peter Stoilov1,{dagger}, Rosette Daoud1, Oliver Nayler2 and Stefan Stamm1,*

1Institute of Biochemistry, University of Erlangen, Fahrstraße 17, 91054 Erlangen, Germany and 2Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland

Received October 15, 2003; Revised December 11, 2003; Accepted December 22, 2003

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.

* To whom correspondence should be addressed at: Institute of Biochemistry, University of Erlangen, Fahrstraße 17, 91054 Erlangen, Germany. Tel: +49 91318524622; Fax: +49 91318524605; Email: stefan{at}stamms-lab.net


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