International Immunology, Vol. 16, No. 1, pp. 65-75,
January 2004
© 2004 Japanese Society for Immunology
Importance of class II transactivator leucine-rich repeats for dominant-negative function and nucleo-cytoplasmic transport
1 Hans-Spemann-Laboratories, Max-Planck-Institut für Immunbiologie, Freiburg D-79108, Germany 2 Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA 3 Present address: Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, Utrecht 3584CG, The Netherlands 4 Present address: Département de Biologie, Université de Sherbrooke, QC J1K 2R1, Canada
Correspondence to: V. Steimle, Département de Biologie, Université de Sherbrooke, 2500 Boulevard Université, Sherbrooke, QC J1K 2R1, Canada. E-mail: viktor.steimle{at}usherbrooke.ca
Transmitting editor: L. Glimcher
Class II transactivator (CIITA), the master regulator of MHC class II (MHC-II) gene transcription, shows a complex behavior in terms of self-association, nucleo-cytoplasmic transport and MHC-II gene transactivation. Here, we analyzed the mechanisms of dominant-negative function and nucleo-cytoplasmic transport of CIITA with emphasis on the role of the C-terminal leucine-rich-repeat (LRR) region in these processes. First, we determined nucleo-cytoplasmic transport of endogenous CIITA and thus validated results obtained with epitope-tagged CIITA constructs. LRR mutations in potential protein–protein contact positions lead to either completely blocked or reduced nuclear import, but can also give rise to increased nuclear export. Surprisingly, N-terminally truncated CIITA mutants show dominant-negative inhibition of wild-type CIITA, whether they are located in the nucleus or in the cytoplasm. Integrity of the LRR is necessary for the dominant-negative function of both types of mutants. LRR mutations are dominant over the effect of an exogenously added N-terminal nuclear localization signal (NLS) leading to cytoplasmic localization. Taken together, our results show that the LRR regulate the function of one or several NLS within CIITA, and control both nuclear import and export. Self-association is not affected in these mutants; we therefore suggest that interaction of the LRR with an unknown protein partner may be necessary for import and transactivation function of CIITA.
Keywords: immune response genes, MHC class II gene regulation, transcriptional regulation
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