Abstract
Using immunoselection, we have isolated 11 independent mutant HT1080 fibrosarcoma cell lines defective in the induction by interferon gamma (IFN-gamma) of the expression of the human leukocyte antigen HLA-DRA. The mutations are recessive and fall into five complementation groups. All the mutants are affected mainly in the expression of major histocompatibility complex class II and invariant-chain genes. Type I mutants (three complementation groups) are completely defective in induction of the invariant-chain and class II HLA-DP, -DQ, -DR, and -DM genes, whereas type II mutants (two complementation groups) induce these genes weakly in response to IFN-gamma, in the order DPB > DRA > invariant chain. The induction by IFN-gamma of the mRNAs for class I, TAP1, LMP7, and 9-27 is partially defective and the induction of the proteins IRF-1 and ICAM-1 is normal in both types of mutants. All the mutants respond normally to IFN-alpha. The mutants are stable and thus can be used to clone the affected genes by reversion.
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- Aguet M., Dembić Z., Merlin G. Molecular cloning and expression of the human interferon-gamma receptor. Cell. 1988 Oct 21;55(2):273–280. doi: 10.1016/0092-8674(88)90050-5. [DOI] [PubMed] [Google Scholar]
- Amaldi I., Reith W., Berte C., Mach B. Induction of HLA class II genes by IFN-gamma is transcriptional and requires a trans-acting protein. J Immunol. 1989 Feb 1;142(3):999–1004. [PubMed] [Google Scholar]
- Barr C. L., Saunders G. F. Interferon-gamma-inducible regulation of the human invariant chain gene. J Biol Chem. 1991 Feb 25;266(6):3475–3481. [PubMed] [Google Scholar]
- Blanar M. A., Boettger E. C., Flavell R. A. Transcriptional activation of HLA-DR alpha by interferon gamma requires a trans-acting protein. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4672–4676. doi: 10.1073/pnas.85.13.4672. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bono M. R., Alcaïde-Loridan C., Couillin P., Letouzé B., Grisard M. C., Jouin H., Fellous M. Human chromosome 16 encodes a factor involved in induction of class II major histocompatibility antigens by interferon gamma. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6077–6081. doi: 10.1073/pnas.88.14.6077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brown A. M., Barr C. L., Ting J. P. Sequences homologous to class II MHC W, X, and Y elements mediate constitutive and IFN-gamma-induced expression of human class II-associated invariant chain gene. J Immunol. 1991 May 1;146(9):3183–3189. [PubMed] [Google Scholar]
- Bénichou B., Strominger J. L. Class II-antigen-negative patient and mutant B-cell lines represent at least three, and probably four, distinct genetic defects defined by complementation analysis. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4285–4288. doi: 10.1073/pnas.88.10.4285. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
- Dale T. C., Imam A. M., Kerr I. M., Stark G. R. Rapid activation by interferon alpha of a latent DNA-binding protein present in the cytoplasm of untreated cells. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1203–1207. doi: 10.1073/pnas.86.4.1203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Day C. E., Jones P. P. The gene encoding the Ia antigen-associated invariant chain (Ii) is not linked to the H-2 complex. Nature. 1983 Mar 10;302(5904):157–159. doi: 10.1038/302157a0. [DOI] [PubMed] [Google Scholar]
- Decker T., Lew D. J., Mirkovitch J., Darnell J. E., Jr Cytoplasmic activation of GAF, an IFN-gamma-regulated DNA-binding factor. EMBO J. 1991 Apr;10(4):927–932. doi: 10.1002/j.1460-2075.1991.tb08026.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Doyle C., Ford P. J., Ponath P. D., Spies T., Strominger J. L. Regulation of the class II-associated invariant chain gene in normal and mutant B lymphocytes. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4590–4594. doi: 10.1073/pnas.87.12.4590. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eades A. M., Litfin M., Rahmsdorf H. J. The IFN-gamma response of the murine invariant chain gene is mediated by a complex enhancer that includes several MHC class II consensus elements. J Immunol. 1990 Jun 1;144(11):4399–4409. [PubMed] [Google Scholar]
- Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Glynne R., Powis S. H., Beck S., Kelly A., Kerr L. A., Trowsdale J. A proteasome-related gene between the two ABC transporter loci in the class II region of the human MHC. Nature. 1991 Sep 26;353(6342):357–360. doi: 10.1038/353357a0. [DOI] [PubMed] [Google Scholar]
- Herrero Sanchez C., Reith W., Silacci P., Mach B. The DNA-binding defect observed in major histocompatibility complex class II regulatory mutants concerns only one member of a family of complexes binding to the X boxes of class II promoters. Mol Cell Biol. 1992 Sep;12(9):4076–4083. doi: 10.1128/mcb.12.9.4076. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Israel A., Kimura A., Fournier A., Fellous M., Kourilsky P. Interferon response sequence potentiates activity of an enhancer in the promoter region of a mouse H-2 gene. Nature. 1986 Aug 21;322(6081):743–746. doi: 10.1038/322743a0. [DOI] [PubMed] [Google Scholar]
- John J., McKendry R., Pellegrini S., Flavell D., Kerr I. M., Stark G. R. Isolation and characterization of a new mutant human cell line unresponsive to alpha and beta interferons. Mol Cell Biol. 1991 Aug;11(8):4189–4195. doi: 10.1128/mcb.11.8.4189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jung V., Jones C., Kumar C. S., Stefanos S., O'Connell S., Pestka S. Expression and reconstitution of a biologically active human interferon-gamma receptor in hamster cells. J Biol Chem. 1990 Feb 5;265(4):1827–1830. [PubMed] [Google Scholar]
- Kara C. J., Glimcher L. H. Regulation of MHC class II gene transcription. Curr Opin Immunol. 1991 Feb;3(1):16–21. doi: 10.1016/0952-7915(91)90070-h. [DOI] [PubMed] [Google Scholar]
- Kelly A. P., Monaco J. J., Cho S. G., Trowsdale J. A new human HLA class II-related locus, DM. Nature. 1991 Oct 10;353(6344):571–573. doi: 10.1038/353571a0. [DOI] [PubMed] [Google Scholar]
- Kelly J. M., Gilbert C. S., Stark G. R., Kerr I. M. Differential regulation of interferon-induced mRNAs and c-myc mRNA by alpha- and gamma-interferons. Eur J Biochem. 1985 Dec 2;153(2):367–371. doi: 10.1111/j.1432-1033.1985.tb09312.x. [DOI] [PubMed] [Google Scholar]
- Levy D. E., Kessler D. S., Pine R., Darnell J. E., Jr Cytoplasmic activation of ISGF3, the positive regulator of interferon-alpha-stimulated transcription, reconstituted in vitro. Genes Dev. 1989 Sep;3(9):1362–1371. doi: 10.1101/gad.3.9.1362. [DOI] [PubMed] [Google Scholar]
- Liou H. C., Boothby M. R., Finn P. W., Davidon R., Nabavi N., Zeleznik-Le N. J., Ting J. P., Glimcher L. H. A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter. Science. 1990 Mar 30;247(4950):1581–1584. doi: 10.1126/science.2321018. [DOI] [PubMed] [Google Scholar]
- Lisowska-Grospierre B., Charron D. J., de Préval C., Durandy A., Griscelli C., Mach B. A defect in the regulation of major histocompatibility complex class II gene expression in human HLA-DR negative lymphocytes from patients with combined immunodeficiency syndrome. J Clin Invest. 1985 Jul;76(1):381–385. doi: 10.1172/JCI111974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Loh J. E., Chang C. H., Fodor W. L., Flavell R. A. Dissection of the interferon gamma-MHC class II signal transduction pathway reveals that type I and type II interferon systems share common signalling component(s). EMBO J. 1992 Apr;11(4):1351–1363. doi: 10.1002/j.1460-2075.1992.tb05180.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Long E. O. In search of a function for the invariant chain associated with Ia antigens. Surv Immunol Res. 1985;4(1):27–34. doi: 10.1007/BF02918583. [DOI] [PubMed] [Google Scholar]
- Long E. O., Mach B., Accolla R. S. Ia-negative B-cell variants reveal a coordinate regulation in the transcription of the HLA class II gene family. Immunogenetics. 1984;19(4):349–353. doi: 10.1007/BF00345408. [DOI] [PubMed] [Google Scholar]
- McKendry R., John J., Flavell D., Müller M., Kerr I. M., Stark G. R. High-frequency mutagenesis of human cells and characterization of a mutant unresponsive to both alpha and gamma interferons. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11455–11459. doi: 10.1073/pnas.88.24.11455. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mirkovitch J., Decker T., Darnell J. E., Jr Interferon induction of gene transcription analyzed by in vivo footprinting. Mol Cell Biol. 1992 Jan;12(1):1–9. doi: 10.1128/mcb.12.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pellegrini S., John J., Shearer M., Kerr I. M., Stark G. R. Use of a selectable marker regulated by alpha interferon to obtain mutations in the signaling pathway. Mol Cell Biol. 1989 Nov;9(11):4605–4612. doi: 10.1128/mcb.9.11.4605. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pestka S., Langer J. A., Zoon K. C., Samuel C. E. Interferons and their actions. Annu Rev Biochem. 1987;56:727–777. doi: 10.1146/annurev.bi.56.070187.003455. [DOI] [PubMed] [Google Scholar]
- Pine R., Decker T., Kessler D. S., Levy D. E., Darnell J. E., Jr Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both beta interferon- and interferon-stimulated genes but is not a primary transcriptional activator of either. Mol Cell Biol. 1990 Jun;10(6):2448–2457. doi: 10.1128/mcb.10.6.2448. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Porter A. C., Chernajovsky Y., Dale T. C., Gilbert C. S., Stark G. R., Kerr I. M. Interferon response element of the human gene 6-16. EMBO J. 1988 Jan;7(1):85–92. doi: 10.1002/j.1460-2075.1988.tb02786.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reich N., Evans B., Levy D., Fahey D., Knight E., Jr, Darnell J. E., Jr Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6394–6398. doi: 10.1073/pnas.84.18.6394. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reid L. E., Brasnett A. H., Gilbert C. S., Porter A. C., Gewert D. R., Stark G. R., Kerr I. M. A single DNA response element can confer inducibility by both alpha- and gamma-interferons. Proc Natl Acad Sci U S A. 1989 Feb;86(3):840–844. doi: 10.1073/pnas.86.3.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reith W., Barras E., Satola S., Kobr M., Reinhart D., Sanchez C. H., Mach B. Cloning of the major histocompatibility complex class II promoter binding protein affected in a hereditary defect in class II gene regulation. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4200–4204. doi: 10.1073/pnas.86.11.4200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schindler C., Shuai K., Prezioso V. R., Darnell J. E., Jr Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. 1992 Aug 7;257(5071):809–813. doi: 10.1126/science.1496401. [DOI] [PubMed] [Google Scholar]
- Sen G. C., Ransohoff R. M. Interferon-induced antiviral actions and their regulation. Adv Virus Res. 1993;42:57–102. doi: 10.1016/s0065-3527(08)60083-4. [DOI] [PubMed] [Google Scholar]
- Stark G. R., Kerr I. M. Interferon-dependent signaling pathways: DNA elements, transcription factors, mutations, and effects of viral proteins. J Interferon Res. 1992 Jun;12(3):147–151. doi: 10.1089/jir.1992.12.147. [DOI] [PubMed] [Google Scholar]
- Trowsdale J., Hanson I., Mockridge I., Beck S., Townsend A., Kelly A. Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transporters. Nature. 1990 Dec 20;348(6303):741–744. doi: 10.1038/348741a0. [DOI] [PubMed] [Google Scholar]
- Tsang S. Y., Nakanishi M., Peterlin B. M. Mutational analysis of the DRA promoter: cis-acting sequences and trans-acting factors. Mol Cell Biol. 1990 Feb;10(2):711–719. doi: 10.1128/mcb.10.2.711. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Uzé G., Lutfalla G., Gresser I. Genetic transfer of a functional human interferon alpha receptor into mouse cells: cloning and expression of its cDNA. Cell. 1990 Jan 26;60(2):225–234. doi: 10.1016/0092-8674(90)90738-z. [DOI] [PubMed] [Google Scholar]
- Wright K. L., Ting J. P. In vivo footprint analysis of the HLA-DRA gene promoter: cell-specific interaction at the octamer site and up-regulation of X box binding by interferon gamma. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7601–7605. doi: 10.1073/pnas.89.16.7601. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Préval C., Lisowska-Grospierre B., Loche M., Griscelli C., Mach B. A trans-acting class II regulatory gene unlinked to the MHC controls expression of HLA class II genes. Nature. 1985 Nov 21;318(6043):291–293. doi: 10.1038/318291a0. [DOI] [PubMed] [Google Scholar]