CATERPILLER 16.2 (CLR16.2), a novel NBD/LRR family member that negatively regulates T cell function.
The newly discovered mammalian CATERPILLER (NOD, NALP, PAN) family of proteins share similarities with the NBD-LRR superfamily of plant disease resistance (R) proteins and are predicted to mediate important immune regulatory function. This report describes the first cloning and characterization of a novel CATERPILLER gene, CLR16.2 that is located on human chromosome 16. The protein encoded by this gene has a typical NBD-LRR configuration. Analysis of CLR16.2 suggests the highest expression among T lymphocytes. Cellular localization studies of CLR16.2 revealed that it is a cytoplasmic protein. Querying microarray studies in the public data base showed that CLR16.2 was significantly (>90%) down-regulated 6 h after anti-CD3 and anti-CD28 stimulation of primary T lymphocytes. Its reduction upon T cell stimulation is consistent with a potential negative regulatory role. Indeed CLR16.2 decreased NF-kappaB, NFAT, and AP-1 induction of reporter gene constructs in response to T cell activation by anti-CD3 and anti-CD28 antibodies or PMA and ionomycin. Following T cell stimulation, the presence of CLR16.2 reduced the levels of the endogenous transcripts for the IL-2 and CD25 proteins that are central in maintaining T cell activation and preventing T cell anergy. This reduction was accompanied by a delay of IkappaBalpha degradation. We propose that CLR16.2 serves to attenuate T cell activation via TCR and co-stimulatory molecules, and its reduction during T cell stimulation allows the ensuing cellular activation.
Conti
Brian J
BJ
Department of Biochemistry and Biophysics and Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Davis
Beckley K
BK
Zhang
Jinghua
J
O'connor
William
W
Williams
Kristi L
KL
Ting
Jenny P-Y
JP
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003001:Cloning, Molecular; D015536:Down-Regulation / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D005810:Multigene Family; D053473:Nod2 Signaling Adaptor Protein; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*
D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C434958:LRRC1 protein, human; D008565:Membrane Proteins; C503285:NLRC3 protein, human; C429018:NOD2 protein, human; C089765:NUBP1 protein, human; D053473:Nod2 Signaling Adaptor Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell