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PR01719

Identifier
MHCIIACTVATR  [View Relations]  [View Alignment]  
Accession
PR01719
No. of Motifs
11
Creation Date
20-MAR-2002
Title
MHC class II transactivator signature
Database References
Literature References
1. MUHLETHALER-MOTTET, A., OTTEN, L,A., STEIMLE, V. AND MACH, B.
Expression of MHC class II molecules in different cellular and functional 
compartments is controlled by differential usage of multiple promoters of 
the transactivator CIITA.
EMBO J. 16 2851-2860 (1997).
 
2. WRIGHT, K.L., CHIN, K., LINHOFF, M., SKINNER, C., BROWN, J., BOSS, J.M., 
STARK, G.R. AND TING, J.P.Y.
CIITA stimulation of transcription factor binding to major histo-
compatibility complex class II and associated promoters in vivo.
PROC.NATL.ACAD.SCI.U.S.A 95 6267-6272 (1998).
 
3. MASTERNAK, K., MUHLEHTALER-MOTTET, A., VILLARD, J., ZUFFEREY, M.,
STEIMLE, V. AND REITH, W.
CIITA is a transcriptional coactivator that is recruited to MHC class II 
promoters by multiple synergistic interactions with an enhanceosome complex.
GENES DEV. 14 1156-1166 (2000).
 
4. SISK, T.J., ROYS, S. AND CHANG, C.H.
Self-association of CIITA and its transactivation potential.
MOL.CELL BIOL. 21 4919-4928 (2001).
 
5. KRETSOVALI. A., SPILIANAKIS, C., DIMAKOPOULOS, A., MAKATOUNAKIS, T. AND 
PAPAMATHEAKIS, J.
Self-association of class II transactivator correlates with its intra-
cellular localization and transactivation.
J.BIOL.CHEM. 276 32191-32197 (2001).
 
6. HOLLING, T.M., STOEP, N., QUINTEN, E. AND ELSEN, P.J.
Activated human T cells accomplish MHC class II expression through T cell-
specific occupation of class II transactivator promoter III.
J.IMMUNOL. 168 763-770 (2002).
 
7. TOWEY, M. AND KELLY, A.P. 
Nuclear localization of CIITA is controlled by a carboxy terminal leucine 
rich repeat region.
MOL.IMMUNOL. 38 627-634 (2002).
 
8. NAGARAJAN, U.M., LOCHAMY, J., CHEN, X., BERESFORD, G.W., NILSEN, R., 
JENSEN, P.E. AND BOSS, J.M.
Class II transactivator is required for maximal expression of HLA-DOB in 
B cells.
J.IMMUNOL. 168 1780-1786 (2002).
 
9. MASTERNAK, K. AND REITH, W.
Promoter-specific functions of CIITA and the MHC class II enhanceosome in 
transcriptional activation.
EMBO J. 21 1379-1388 (2002).

Documentation
Class II transactivator (CIITA) determines the level, cell type specificity,
inducibility and extinction of MHC-II expression. CIITA is also the 
obligatory mediator of INF-gamma inducible MHC-II expression. Thus control
of MHC-II expression is ultimately dependent on the control of expression
of the CIITA gene itself. Defective CIITA has been shown to be responsible
for one class of base lymphocyte syndrome (BLS). BLS is an often fatal 
genetic defect, characterised by severe immunodeficiency as a result of 
failure to express MHC class II genes. Expression of CIITA is controlled by
four independent CIITA promoters, leading to CIITA transcripts with four 
distinct first exons. The individual promoters are used in an alternative
and tissue-specific manner. CIITA promoter (CIITA-P)I is the promoter used
in dentritic cells; CIITA-PII is expressed at insignificant levels and is 
as yet functionally poorly understood; CIITA-PIII is constitutively
expressed in B lymphocytes and can drive CIITA expression after INF-gamma
stimulation in a number of different cell types, including endothelial cells
and fibroblasts; and CIITA-PIV is the principal INF-gamma-inducible promoter.
The cellular and temporal diversity in MHC class II expression is thus 
regulated via the different usage of the CIITA promoters [1-3,6-8].
 
Transcription of the MHC class II and related genes is regulated by a common
set of transcription factors. These include REX, X2BP/CREB, NF-Y and CIITA,
which all bind a short-150bp regulatory module conserved in the promoter 
proximal regions of all MHC-II genes. This regulatory module consists of 
four cis-acting sequences and is known as the W-X-X2-Y region. Binding of
REX, X2BP and NF-Y to the promoter DNA is highly cooperative and results in
the formation of a remarkably stable higher-order nucleoprotein complex that
can be regarded as the MHC-II enhanceosome. However, the above three factors
are expressed ubiquitously and in an apparently unregulated manner, implying
that they do not provide the regulatory function necessary for cell-specific
and inducible MHCII expression. It follows that enhanceosome assembly is
essential but not sufficient for MHC-II expression, which ultimately depends
on CIITA, a highly regulated master control factor that is recruited to the
enhanceosome by multiple weak interactions between its C-terminal moiety and
several different components of the MHC-II enhanceosome [1-3]. 
 
CIITA contains four domains: acidic (A), proline-serine-threonine-rich (PST), 
GTP-binding (GBD), and leucine-rich repeat (LRR). All of these are required
to activate the MHC class II promoter. The acidic transcriptional activation
domain interacts with TAFII32. Recruitment of the coactivator protein CBP by
the acidic domain has also been shown to lead to synergistic activation of
MHC class II promoters and the repression of the interleukin-4 promoter. The
PST domain is essential for CIITA function, but its exact role remains 
unknown. The central region containing the GTP-binding and LXXLL motifs 
plays an important role in CIITA self-association. This region interacts 
with itself, the N-terminal domain of CIITA (A/PST) and C-terminal LRR. In 
addition to their role in CIITA self-association, which is generally 
necessary for the association of the protein with the import machinery, both
GBD (where GTP binding is believed to cause a conformational change  
compatible with nuclear translocation) and LRR domains have been shown to
play important roles in the nuclear localisation of CIITA. Generally, 
translocation of a protein from the cytoplasm into the nucleus is dependent
on the presence of nuclear localisation signals (NLSs) within the protein. 
NLSs tend to be rich in basic residues that mediate binding to members of 
the importin alpha family of proteins. In human CIITA, the 110-residue 
region from 336-444 appears to contain a NLS. Export of a protein depends 
on the presence of a specific export signal (NES). NESs are short leucine-
rich motifs - in CIITA, they have the consensus LXXXLXXLXL, and are
localised in the N- and C-terminal regions [4,5,7].
 
Numerous in vitro and functional studies have implicated CIITA in multiple
steps of the transcriptional activation process: e.g., (i) it may facilitate
chromatin remodelling, as it interacts with histone acetyltransferases;
moreover, it has intrinsic acetyltransferase activity; (ii) it interacts
with the general transcription factors TFIIB, HTAFII32 and HTAFI70, implying
that it may recruit the transcriptional apparatus directly; (iii) it
interacts with TFIIH and P-TEFb, and may therefore enhance promoter
clearance and transcription elongation. An implicit picture emerging from
these studies is that CIITA activates transcription single-handedly, while
the role of the MHCII enhanceosome is relegated to specific DNA sequence
recognition and CIITA recruitment [9].
 
MHCIIACTVATR is an 11-element fingerprint that provides a signature for the
CIITA transcriptional coactivators. The fingerprint was derived from an
initial alignment of 5 sequences: the motifs were drawn from conserved 
regions spanning virtually the full alignment length - motifs 1-4 and 5-7
span the two nuclear export regions, motifs 1,6 and 9 containing the NES 
consensus, LXXXLXXLXL. Two iterations on SPTR39_17f were required to
reach convergence, at which point a true set comprising 8 sequences was 
identified. A single partial match was also found, Q29704, the human RJ2.2.5 
mutant, a non-functional CIITA that matches motifs 1-4, the first of the 
two nuclear export regions.
Summary Information
   8 codes involving 11 elements
0 codes involving 10 elements
0 codes involving 9 elements
0 codes involving 8 elements
0 codes involving 7 elements
0 codes involving 6 elements
0 codes involving 5 elements
1 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
1188888888888
1000000000000
900000000000
800000000000
700000000000
600000000000
500000000000
411110000000
300000000000
200000000000
1234567891011
True Positives
C2TA_HUMAN    C2TA_MOUSE    O78109        Q29675        
Q9GJD8 Q9GJD9 Q9GJE0 Q9TPP1
True Positive Partials
Codes involving 4 elements
Q29704
Sequence Titles
C2TA_HUMAN  MHC CLASS II TRANSACTIVATOR CIITA - Homo sapiens (Human). 
C2TA_MOUSE MHC CLASS II TRANSACTIVATOR CIITA - Mus musculus (Mouse).
O78109 MHC CLASS II TRANSACTIVATOR CIITA FORM IV - Mus musculus (Mouse).
Q29675 MHC CLASS II TRANSACTIVATOR CIITA - Homo sapiens (Human).
Q9GJD8 MHC CLASS II TRANSACTIVATOR TYPE IV - Rattus norvegicus (Rat).
Q9GJD9 MHC CLASS II TRANSACTIVATOR TYPE III - Rattus norvegicus (Rat).
Q9GJE0 MHC CLASS II TRANSACTIVATOR TYPE I - Rattus norvegicus (Rat).
Q9TPP1 MHC CLASS II TRANSACTIVATOR CIITA FORM I - Mus musculus (Mouse).

Q29704 CLASS II MHC MUTANT RJ2.2.5 - Homo sapiens (Human).
Scan History
SPTR39_17f 2  100  NSINGLE    
Initial Motifs
Motif 1  width=12
Element Seqn Id St Int Rpt
YLELLNSDADPL Q9GJD9 31 31 -
YLELLNSDADPL C2TA_MOUSE 34 34 -
YLELLNSDADPL Q9TPP1 111 111 -
YLELLNSDADPL C2TA_HUMAN 34 34 -
YLELLNSDADPL Q29675 34 34 -

Motif 2 width=14
Element Seqn Id St Int Rpt
YDQMDLAGEEEIEL Q9GJD9 48 5 -
YDQMDLAGEEEIEL C2TA_MOUSE 51 5 -
YDQMDLAGEEEIEL Q9TPP1 128 5 -
YDQMDLAGEEEIEL C2TA_HUMAN 51 5 -
YDQMDLAGEEEIEL Q29675 51 5 -

Motif 3 width=15
Element Seqn Id St Int Rpt
DEETREAYANIAELD Q9GJD9 85 23 -
DEETREAYANIAELD C2TA_MOUSE 88 23 -
DEETREAYANIAELD Q9TPP1 165 23 -
DEETREAYANIAELD C2TA_HUMAN 88 23 -
DEETREAYANIAELD Q29675 88 23 -

Motif 4 width=17
Element Seqn Id St Int Rpt
QYVFQDTQLEGLSKDLF Q9GJD9 100 0 -
QYVFQDTQLEGLSKDLF C2TA_MOUSE 103 0 -
QYVFQDTQLEGLSKDLF Q9TPP1 180 0 -
QYVFQDSQLEGLSKDIF C2TA_HUMAN 103 0 -
QYVFQDSQLEGLSKDIF Q29675 103 0 -

Motif 5 width=18
Element Seqn Id St Int Rpt
PDRVLLILDAFEELEAQD Q9GJD9 437 320 -
PDRVLLILDAFEELEAQD C2TA_MOUSE 439 319 -
PDRVLLILDAFEELEAQD Q9TPP1 516 319 -
PDRVLLILDAFEELEAQD C2TA_HUMAN 491 371 -
PDRVLLILDAFEELEAQD Q29675 443 323 -

Motif 6 width=22
Element Seqn Id St Int Rpt
EPCSLRGLLAGLFQRKLLRGCT Q9GJD9 467 12 -
EPCSLRGLLAGIFQRKLLRGCT C2TA_MOUSE 469 12 -
EPCSLRGLLAGIFQRKLLRGCT Q9TPP1 546 12 -
EPCSLRGLLAGLFQKKLLRGCT C2TA_HUMAN 521 12 -
EPCSLRGLLAGLFQKKLLRGCT Q29675 473 12 -

Motif 7 width=21
Element Seqn Id St Int Rpt
LTARPRGRLAQSLSKADAIFE Q9GJD9 491 2 -
LTARPRGRLAQSLSKADAIFE C2TA_MOUSE 493 2 -
LTARPRGRLAQSLSKADAIFE Q9TPP1 570 2 -
LTARPRGRLVQSLSKADALFE C2TA_HUMAN 545 2 -
LTARPRGRLVQSLSKADALFE Q29675 497 2 -

Motif 8 width=26
Element Seqn Id St Int Rpt
SPPGALVELAKLAWELGRRHQSTLQE Q9GJD9 598 86 -
SPPGALVELAKLAWELGRRHQSTLQE C2TA_MOUSE 600 86 -
SPPGALVELAKLAWELGRRHQSTLQE Q9TPP1 677 86 -
SPPGALAELAKLAWELGRRHQSTLQE C2TA_HUMAN 652 86 -
SPPGALAELAKLAWELGRRHQSTLQE Q29675 604 86 -

Motif 9 width=13
Element Seqn Id St Int Rpt
SFLLQCFLGAVWL Q9GJD9 653 29 -
SFLLQCFLGAVWL C2TA_MOUSE 658 32 -
SFLLQCFLGAVWL Q9TPP1 735 32 -
SFLLQCFLGALWL C2TA_HUMAN 710 32 -
SFLLQCFLGALWL Q29675 662 32 -

Motif 10 width=18
Element Seqn Id St Int Rpt
KDKELPQYLALTPRKKRP Q9GJD9 672 6 -
KDKELPQYLALTPRKKRP C2TA_MOUSE 677 6 -
KDKELPQYLALTPRKKRP Q9TPP1 754 6 -
KDKELPQYLALTPRKKRP C2TA_HUMAN 729 6 -
KDKELPQYLALTPRKKRP Q29675 681 6 -

Motif 11 width=13
Element Seqn Id St Int Rpt
LPGHLSFLGTRLT Q9GJD9 772 82 -
LPGHLSFLGTRLT C2TA_MOUSE 777 82 -
LPGHLSFLGTRLT Q9TPP1 854 82 -
LPGRLSFLGTRLT C2TA_HUMAN 829 82 -
LPGRLSFLGTRLT Q29675 781 82 -
Final Motifs
Motif 1  width=12
Element Seqn Id St Int Rpt
YLELLNSDADPL Q9GJD8 10 10 -
YLELLNSDADPL Q9GJE0 111 111 -
YLELLNSDADPL Q9GJD9 31 31 -
YLELLNSDADPL C2TA_MOUSE 34 34 -
YLELLNSDADPL Q9TPP1 111 111 -
YLELLNSDADPL O78109 10 10 -
YLELLNSDADPL C2TA_HUMAN 34 34 -
YLELLNSDADPL Q29675 34 34 -

Motif 2 width=14
Element Seqn Id St Int Rpt
YDQMDLAGEEEIEL Q9GJD8 27 5 -
YDQMDLAGEEEIEL Q9GJE0 128 5 -
YDQMDLAGEEEIEL Q9GJD9 48 5 -
YDQMDLAGEEEIEL C2TA_MOUSE 51 5 -
YDQMDLAGEEEIEL Q9TPP1 128 5 -
YDQMDLAGEEEIEL O78109 27 5 -
YDQMDLAGEEEIEL C2TA_HUMAN 51 5 -
YDQMDLAGEEEIEL Q29675 51 5 -

Motif 3 width=15
Element Seqn Id St Int Rpt
DEETREAYANIAELD Q9GJD8 64 23 -
DEETREAYANIAELD Q9GJE0 165 23 -
DEETREAYANIAELD Q9GJD9 85 23 -
DEETREAYANIAELD C2TA_MOUSE 88 23 -
DEETREAYANIAELD Q9TPP1 165 23 -
DEETREAYANIAELD O78109 64 23 -
DEETREAYANIAELD C2TA_HUMAN 88 23 -
DEETREAYANIAELD Q29675 88 23 -

Motif 4 width=17
Element Seqn Id St Int Rpt
QYVFQDTQLEGLSKDLF Q9GJD8 79 0 -
QYVFQDTQLEGLSKDLF Q9GJE0 180 0 -
QYVFQDTQLEGLSKDLF Q9GJD9 100 0 -
QYVFQDTQLEGLSKDLF C2TA_MOUSE 103 0 -
QYVFQDTQLEGLSKDLF Q9TPP1 180 0 -
QYVFQDTQLEGLSKDLF O78109 79 0 -
QYVFQDSQLEGLSKDIF C2TA_HUMAN 103 0 -
QYVFQDSQLEGLSKDIF Q29675 103 0 -

Motif 5 width=18
Element Seqn Id St Int Rpt
PDRVLLILDAFEELEAQD Q9GJD8 416 320 -
PDRVLLILDAFEELEAQD Q9GJE0 517 320 -
PDRVLLILDAFEELEAQD Q9GJD9 437 320 -
PDRVLLILDAFEELEAQD C2TA_MOUSE 439 319 -
PDRVLLILDAFEELEAQD Q9TPP1 516 319 -
PDRVLLILDAFEELEAQD O78109 415 319 -
PDRVLLILDAFEELEAQD C2TA_HUMAN 491 371 -
PDRVLLILDAFEELEAQD Q29675 443 323 -

Motif 6 width=22
Element Seqn Id St Int Rpt
EPCSLRGLLAGLFQRKLLRGCT Q9GJD8 446 12 -
EPCSLRGLLAGLFQRKLLRGCT Q9GJE0 547 12 -
EPCSLRGLLAGLFQRKLLRGCT Q9GJD9 467 12 -
EPCSLRGLLAGIFQRKLLRGCT C2TA_MOUSE 469 12 -
EPCSLRGLLAGIFQRKLLRGCT Q9TPP1 546 12 -
EPCSLRGLLAGIFQRKLLRGCT O78109 445 12 -
EPCSLRGLLAGLFQKKLLRGCT C2TA_HUMAN 521 12 -
EPCSLRGLLAGLFQKKLLRGCT Q29675 473 12 -

Motif 7 width=21
Element Seqn Id St Int Rpt
LTARPRGRLAQSLSKADAIFE Q9GJD8 470 2 -
LTARPRGRLAQSLSKADAIFE Q9GJE0 571 2 -
LTARPRGRLAQSLSKADAIFE Q9GJD9 491 2 -
LTARPRGRLAQSLSKADAIFE C2TA_MOUSE 493 2 -
LTARPRGRLAQSLSKADAIFE Q9TPP1 570 2 -
LTARPRGRLAQSLSKADAIFE O78109 469 2 -
LTARPRGRLVQSLSKADALFE C2TA_HUMAN 545 2 -
LTARPRGRLVQSLSKADALFE Q29675 497 2 -

Motif 8 width=26
Element Seqn Id St Int Rpt
SPPGALVELAKLAWELGRRHQSTLQE Q9GJD8 577 86 -
SPPGALVELAKLAWELGRRHQSTLQE Q9GJE0 678 86 -
SPPGALVELAKLAWELGRRHQSTLQE Q9GJD9 598 86 -
SPPGALVELAKLAWELGRRHQSTLQE C2TA_MOUSE 600 86 -
SPPGALVELAKLAWELGRRHQSTLQE Q9TPP1 677 86 -
SPPGALVELAKLAWELGRRHQSTLQE O78109 576 86 -
SPPGALAELAKLAWELGRRHQSTLQE C2TA_HUMAN 652 86 -
SPPGALAELAKLAWELGRRHQSTLQE Q29675 604 86 -

Motif 9 width=13
Element Seqn Id St Int Rpt
SFLLQCFLGAVWL Q9GJD8 632 29 -
SFLLQCFLGAVWL Q9GJE0 733 29 -
SFLLQCFLGAVWL Q9GJD9 653 29 -
SFLLQCFLGAVWL C2TA_MOUSE 658 32 -
SFLLQCFLGAVWL Q9TPP1 735 32 -
SFLLQCFLGAVWL O78109 634 32 -
SFLLQCFLGALWL C2TA_HUMAN 710 32 -
SFLLQCFLGALWL Q29675 662 32 -

Motif 10 width=18
Element Seqn Id St Int Rpt
KDKELPQYLALTPRKKRP Q9GJD8 651 6 -
KDKELPQYLALTPRKKRP Q9GJE0 752 6 -
KDKELPQYLALTPRKKRP Q9GJD9 672 6 -
KDKELPQYLALTPRKKRP C2TA_MOUSE 677 6 -
KDKELPQYLALTPRKKRP Q9TPP1 754 6 -
KDKELPQYLALTPRKKRP O78109 653 6 -
KDKELPQYLALTPRKKRP C2TA_HUMAN 729 6 -
KDKELPQYLALTPRKKRP Q29675 681 6 -

Motif 11 width=13
Element Seqn Id St Int Rpt
LPGHLSFLGTRLT Q9GJD8 751 82 -
LPGHLSFLGTRLT Q9GJE0 852 82 -
LPGHLSFLGTRLT Q9GJD9 772 82 -
LPGHLSFLGTRLT C2TA_MOUSE 777 82 -
LPGHLSFLGTRLT Q9TPP1 854 82 -
LPGHLSFLGTRLT O78109 753 82 -
LPGRLSFLGTRLT C2TA_HUMAN 829 82 -
LPGRLSFLGTRLT Q29675 781 82 -