NOSTRINbeta--a shortened NOSTRIN variant with a role in transcriptional regulation.
We recently observed that a novel, shortened variant of eNOS trafficking inducer (NOSTRIN) is expressed in cirrhotic liver. This shortened variant (NOSTRINbeta) lacks the first 78 amino acids of full-length NOSTRIN (NOSTRINalpha) and thus a substantial part of its F-BAR domain. In contrast to NOSTRINalpha, NOSTRINbeta mainly localizes to the cell nucleus. In this study, we show that nuclear import of NOSTRINbeta depends on two nuclear localization signals (aa 32-36: KKRK and aa 57-61: KAKKK). Each of the sequences is independently functional, but both are required to sustain nuclear localization of NOSTRINbeta. Export of NOSTRINbeta from the nucleus is facilitated by a CRM1-dependent mechanism relying on the nuclear export sequence LELEKERIQL (aa 135-145). Unlike NOSTRINbeta, the full-length variant NOSTRINalpha was conspicuously absent from the nucleus. This is most likely because of the fact that its N-terminal F-BAR domain, which is truncated in NOSTRINbeta, facilitates association with cellular membranes. NOSTRINbeta directly binds to the 5'-regulatory region of the NOSTRIN gene (bp -200 to -1), and overexpression of NOSTRINbeta strongly decreases transcription of a reporter gene under control of this DNA region. Taken together, our results suggest that nuclear NOSTRINbeta may negatively regulate transcription of the NOSTRIN gene.
Wiesenthal
Anja
A
Institute of Biochemistry II and Cluster of Excellence-Macromolecular Complexes, University of Frankfurt Medical School, Theodor-Stern-Kai 7, Frankfurt, Germany.
Hoffmeister
Meike
M
Siddique
Masood
M
Kovacevic
Igor
I
Oess
Stefanie
S
Müller-Esterl
Werner
W
Siehoff-Icking
Ann
A
D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C470345:NOSTRIN protein, human; D012333:RNA, Messenger; D012097:Repressor Proteins