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Molecular and Cellular Biology, August 2008, p. 5014-5026, Vol. 28, No. 16
0270-7306/08/$08.00+0     doi:10.1128/MCB.00640-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

MPYS, a Novel Membrane Tetraspanner, Is Associated with Major Histocompatibility Complex Class II and Mediates Transduction of Apoptotic Signals {triangledown} ,{dagger}

Lei Jin,1 Paul M. Waterman,1 Karen R. Jonscher,2 Cindy M. Short,1 Nichole A. Reisdorph,1 and John C. Cambier1*

Integrated Department of Immunology, University of Colorado School of Medicine and National Jewish Medical and Research Center, Denver, Colorado 80206,1 Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, Colorado 802622

Received 19 April 2008/ Accepted 30 May 2008

Although the best-defined function of type II major histocompatibility complex (MHC-II) is presentation of antigenic peptides to T lymphocytes, these molecules can also transduce signals leading alternatively to cell activation or apoptotic death. MHC-II is a heterodimer of two transmembrane proteins, each containing a short cytoplasmic tail that is dispensable for transduction of death signals. This suggests the function of an undefined MHC-II-associated transducer in signaling the death response. Here we describe a novel plasma membrane tetraspanner (MPYS) that is associated with MHC-II and mediates its transduction of death signals. MPYS is unusual among tetraspanners in containing an extended C-terminal cytoplasmic tail (~140 amino acids) with multiple embedded signaling motifs. MPYS is tyrosine phosphorylated upon MHC-II aggregation and associates with inositol lipid and tyrosine phosphatases. Finally, MHC class II-mediated cell death signaling requires MPYS-dependent activation of the extracellular signal-regulated kinase signaling pathway.

* Corresponding author. Mailing address: University of Colorado School of Medicine and National Jewish Medical and Research Center, Integrated Department of Immunology, Room 1004 Goodman Building, 1400 Jackson St., Denver, CO 80206. Phone: (303) 398-1352. Fax: (303) 270-2325. E-mail: cambierj{at}njc.org

{triangledown} Published ahead of print on 16 June 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2008, p. 5014-5026, Vol. 28, No. 16
0270-7306/08/$08.00+0     doi:10.1128/MCB.00640-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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