Abstract:
: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.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Stoilov P,Daoud R,Nayler O,Stamm Sdoi
10.1093/hmg/ddh051subject
Has Abstractpub_date
2004-03-01 00:00:00pages
509-24issue
5eissn
0964-6906issn
1460-2083pii
ddh051journal_volume
13pub_type
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