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Molecular and Cellular Biology, September 2004, p. 7503-7513, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7503-7513.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The N-Terminal Regulatory Domain of Stp1p Is Modular and, Fused to an Artificial Transcription Factor, Confers Full Ssy1p-Ptr3p-Ssy5p Sensor Control

Claes Andréasson and Per O. Ljungdahl*

Ludwig Institute for Cancer Research, Stockholm, Sweden

Received 8 March 2004/ Returned for modification 26 April 2004/ Accepted 10 June 2004

Stp1p and Stp2p are homologous and redundant transcription factors that are synthesized as latent cytoplasmic proteins with N-terminal regulatory domains. In response to extracellular amino acids, the plasma membrane-localized Ssy1p-Ptr3p-Ssy5p (SPS) sensor induces an endoproteolytic processing event that cleaves away the N-terminal regulatory domains. The shorter forms of Stp1p and Stp2p are targeted to the nucleus, where they bind and activate the transcription of amino acid permease genes. A novel genetic screen, specifically designed to search for rare mutations that affect the SPS-sensing pathway, identified the F-box protein Grr1p as an obligatory factor required for Stp1p/Stp2p processing. Additionally, we have found that a null mutation in the ASI1 (amino acid sensor-independent) gene enables full-length unprocessed Stp1p/Stp2p to enter the nucleus and derepress SPS sensor-dependent genes. The N-terminal domains of Stp1p/Stp2p contain two conserved motifs that are required for proper nuclear exclusion and proteolytic processing. These motifs function in parallel; mutations that abolish processing inhibit signaling, whereas mutations that interfere with cytoplasmic retention result in constitutive derepression of SPS sensor-regulated genes independently of processing. The N-terminal domain of Stp1p is functionally autonomous and transferable to other transcription factors, where its presence confers ASI1-dependent nuclear exclusion and SPS sensor-induced proteolytic processing.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, Box 240, S-171 77 Stockholm, Sweden. Phone: 46 8 524 87108. Fax: 46 8 33 28 12. E-mail: plju{at}licr.ki.se.

Molecular and Cellular Biology, September 2004, p. 7503-7513, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7503-7513.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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