CD335 NCR1 (natural cytotoxicity triggering receptor 1), NKp46 (natural killer cell p46-related protein), NK-p46, LY94 (lymphocyte antigen 94 homolog)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
NK Cell
46 / 46

Expression
CD335 is expressed selectively on resting and activated NK cells.

Structure
MOLECULAR FAMILY NAME: Belongs to the immunoglobulin gene family.

CD335 is a single-pass type-1 283 aa transmembrane glycoprotein.  It contains a 21 aa signal sequence, a 237 aa extracellular domain which contains 2 cysteine-bridged Ig-like CD2-type domains, 2 O-linked glycosylation sites and 1 potential N-linked glycosylation site, short 21 aa transmembrane domain which is connected by a stem from the extracellular domain and contains a charged arginine that is predicted to associate with the CD3ζ chain (CD247) and an 25 aa intracellular cytoplasmic domain which has no known ITIMs signaling motifs.  The association with CD3ζ which bears an ITIM allows the delivery of activation signals. When CD335 is expressed in COS-7, anti-CD335 immunoprecipitates a 46 kDa surface molecule.  It is a novel NK-specific molecule belonging to a group of receptors collectively termed the natural cytotoxicity receptors (NCR) within the Ig superfamily.   

MOLECULAR MASS

POST-TRANSCRIPTIONAL MODIFICATION

Alternatively splicing yields 5 different isoforms.  Apart from the full length molecule, the remaining four isoforms all lack the regions of the extracellular domain with the exception of the membrane proximal Ig-like domain which has been observed.

POST-TRANSLATIONAL MODIFICATION
 
CD335 has one potential N-linked glycosylation site and 2 O-linked glycosylation sites.


Ligands
LIGANDS AND MOLECULE ASSOCIATED WITH CD335

CD335 associates with the ITIM-containing CD3ζ and FcεRIγ (FCERIG).  CD335 binds to influenza virus hemagglutinin (HA) and the HA-neuraminidase of the Sendai virus.  Recent studies have identified heparan sulphate proteoglycans (HSPGs) on the surface of tumor cells as ligands of CD335.

Function
CD335 is a major lysis receptor for NK cells and mediated direct lysis of autologous virus-infected cells and tumor cells.  Sialic acid residues on CD335 are thought to be involved in viral hemagglutinins and heparan sulfate proteoglycans.  CD335 lacks any cytoplasmic signaling motifs but associates with CD3ζ chain which bears an ITIM and delivers activating signals.  The surface density of CD335, CD336 and CD337 correlates with the magnitude of NK-cell cytolytic activity against target cells which mediate tumor cell lysis.  Variation in the surface density of these molecules occurs within and between individuals.  Prolactin can upregulate CD335 and CD337 expression and cortisol downregulates expression of both natural cytotoxicity receptor (NCRs).  CD335 mediated cytotoxicity of tumor cells is suicidal for NK cells as CD337 engagement with tumor cell ligands leads to upregulation of FasL protein synthesis and release.  FasL ligation of Fas on the NK cell surface triggers caspase 3-dependent apoptosis.  These receptors trigger NK cells activation upon recognition of non-MHC and HLA ligands promoting lysis of the tumor target cell.  Analysis in various lymphoid and myelomonocytic cells revealed that CD335 expression is confined to NK cells.  

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD335 IN INTACT ANIMAL

Exposure to Mycobacterium tuberculosis often results in infection manifested by a T-cell dependent positive tuberculin skin test.  Some individuals who have had prolinged exposure do not develop a positive TST, sugesting that innate immunity mediated by NK cells control the infection.  It has been shown that NK cell expressing CD335, but not those expressing CD336, from healthy TST-positive and TST-negative donors efficiently lysed M. tuberculosis infected autologous monocytes is an apparently cytokine-independent manner.  NK cells from tuberulosis patients mediated significantly less lysis against such cells or against K562 erythroleukemia cells, in spite of having comparable numbers of circulating CD56 positive NK cells.  Infection of monocytes did not result in reduced expression of MHC class I molecules, and NK cell lytic activity was not due to an observed enhanced production of IL-18 or IFN-γ by donor NK cells.  RT-PCR analysis revealed that upregulated CD335, but not CD336, expression after M. tuberculosis infected monocytes by healthy donors, but not by tuberculosis patients.  NK-cell cytotoxic activity could be blocked by anti-CD335 without affecting cell viability.  It has been concluded that CD335 participates in NK cell mediated lysis of cells infected with an intracellular bacterium and that reduced functional capacity of NK cell is associated with severe manifectations of infectious disease.

Comments
MOLECULAR INTERACTIONS-
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD335: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD335: No information.

ADDITIONAL INSIGHTS

For further information see Moretta, A. et al (2001) Ann. Rev. Immunol. 19: 197-223.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 9437O76036
Antibodies

Revised June 25, 2008


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