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

Abstract

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.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

We thank Ryan Young and Yosef Refaeli for providing the shRNA knockdown protocol and the pLL3.7 vector, Aimee Pugh-Bernard for the K46 cDNA library, and Rick Willis for bone marrow-derived dendritic cells.

This work is supported by a grant from the National Institute of Allergy and Infectious Diseases, 5R01AI020519-22, to J.C.C. J.C.C. is an Ida and Cecil Green Professor of Immunology. The CNRU Mass Spectrometry Core is supported by NIH/NIDDK grant P30 DK048520.

We have no conflicting interests to declare.