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 (ϳ140 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.

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

“…VISA is constitutively associated with another mitochondrion-associated adapter protein, MITA/STING, which is also essential for virus-triggered signaling. [11][12][13] VISA is associated with TRAF2 and TRAF6 through its TRAF interaction motifs. 7 TRAF2 and TRAF6 facilitate K63-linked polyubiquitination of receptorinteracting protein and NF-kB essential modulator, respectively.…”

Binding of bacterial secondary messenger molecule c di-GMP is a STING operation

“…Based on the N-terminal sequence consisting of Methionine, Proline, Tyrosine and Serine, the protein was named MPYS. Confocal microscopy of STING-GFP fusion constructs over expressed in K46 cells identified a majority of the protein localized to the mitochondrion (Jin et al, 2008).…”

“…STING was first discovered in K46 cells as an MHC class II associated protein that participated in the relay of death signals (Jin et al, 2008). STING was essential for ERK mediated, but c Src independent, apoptosis triggered by MHC class II molecules.…”

“…STING is a 379 amino acid long, 42 kDa transmembrane protein (Jin et al, 2008). The N-terminus of STING is predicted to thread the membrane 4 or 5 times, while the C-terminus is cytosolic (Ishikawa and Barber, 2008;Jin et al, 2008;Zhong et al, 2008;Sun et al, 2009).…”

“…The N-terminus of STING is predicted to thread the membrane 4 or 5 times, while the C-terminus is cytosolic (Ishikawa and Barber, 2008;Jin et al, 2008;Zhong et al, 2008;Sun et al, 2009). Information on the exact domain boundaries for STING is lacking.…”