These data indicate that the aged Nrf2-deficient female mice develop lupus-like autoimmune nephritis and suggest that nrf2 is one of the genes determining susceptibility to autoimmune disease. Analysis of nephritis in the Nrf2-deficient female mouse may clarify the mechanisms leading to the development of lupus disease.

No abstract

Src-family tyrosine kinases (SFKs), which are non-receptor-type tyrosine kinases, consist of proto-oncogene products and structurally related proteins and include at least eight highly homologous proteins: Src, Lyn, Fyn, Yes, Fgr, Hck, Lck and Blk (Brown and Cooper, 1996;Thomas and Brugge, 1997). SFKs are activated by various stimuli, including growth factors and adhesion proteins, and are involved in a wide range of signaling events at the plasma membrane, resulting in cell proliferation, differentiation, migration, and cell-shape changes. Src, Yes, Lyn and Fyn are widely expressed in a variety of cell types, whereas Blk, Fgr, Hck and Lck are found primarily in hematopoietic cells (Bolen and Brugge, 1997;Thomas and Brugge, 1997).SFKs are composed of (1) an N-terminal Src homology (SH) 4 domain that contains lipid modification sites; (2) a poorly conserved 'unique' domain; (3) an SH3 domain that can bind to specific proline-rich sequences; (4) an SH2 domain that can bind to specific sites of tyrosine phosphorylation; (5) an SH1 tyrosine kinase catalytic domain; and (6) a negative regulatory tail for autoinhibition of kinase activity (Brown and Cooper, 1996;Thomas and Brugge, 1997). All members of the Src family are cotranslationally myristoylated at Gly2 and, with the exception of Src and Blk, are also post-translationally palmitoylated at Cys3, Cys5 or Cys6 (Paige et al., 1993;Alland et al., 1994;Koegl et al., 1994;Resh, 1994; Shenoy-Scaria et al., 1994; Kasahara et al., 2007a). Fatty acylation of SFKs has been shown to influence their interactions with cell membranes (McCabe and Berthiaume, 1999;Resh, 1999) and as a consequence their intracellular distribution.It is generally thought that SFKs are predominantly located at the cytoplasmic face of the plasma membrane through posttranslational myristoylation, usually with subsequent palmitoylation, but in fact, appreciable fractions are found at in variety of intracellular locations, such as endosomes, secretory granules or phagosomes and the Golgi complex (Kaplan et al., 1992;Mohn et al., 1995;Brown and Cooper, 1996;Thomas and Brugge, 1997;Kasahara et al., 2004). Although distinctive localizations of SFK members have been implicated in their specific functions, the mechanism that underlies the targeting of SFKs to their specific locations remains to be elucidated.We recently showed that Lyn, a palmitoylated SFK, is exocytosed to the plasma membrane via the Golgi region along the secretory pathway (Kasahara et al., 2004). More recently, we demonstrated that Src, a non-palmitoylated SFK, rapidly moves between the plasma membrane and late endosomes or lysosomes, and that mutation of Cys3 in Lyn allows Lyn to traffic in a similar manner to Src (Kasahara et al., 2007a), indicating the importance of palmitoylation for distinct trafficking between Lyn and Src.In this study, we investigate the localization and trafficking of other ubiquitously expressed SFKs, such as Yes and Fyn. We demonstrate that Lyn and Yes, which are monopalmitoylated SFKs, Src-family tyrosine kin...

Effects of transforming growth factor beta (TGF-beta) on IgA production by LPS-stimulated B cells have been studied. TGF-beta itself could augment polyclonal IgA production in concomitant inhibition of polyclonal IgM and IgG1 production. Furthermore, TGF-beta and IL-5 additively augmented IgA production. TGF-beta exerted its activity early in the culture (by 2 d in a 5-d culture) and IL-5 was required late in the culture. Surface IgA- (sIgA-) B cells responded to TGF-beta for the development of IgA-secreting cells. By contrast, sIgA+ B cells, but not sIgA- B cells, responded to IL-5 for IgA production. These results suggest that TGF-beta has a differential role in the induction of IgA production from IL-5 on murine-activated B cells.

We report 10 cases of glomerulonephritis following methicillin-resistant Staphylococcus aureus (MRSA) infection. The clinical features of this syndrome were an abrupt or insidious onset of rapidly progressive glomerulonephritis (RPGN) with nephrotic syndrome and occasionally purpura, following MRSA infection. The renal histologic findings showed a variety of types of proliferative glomerulonephritis with varying degrees of crescent formation; immunofluorescence revealed of glomerular deposition of IgA, IgG, and C3. Laboratory findings showed polyclonal increases of serum IgA and IgG, with high levels of circulating immune complexes (ICs). Increased numbers of DR+CD4+, and DR+CD8+T cells were observed in the peripheral circulation, with a high frequency of T cell receptor (TCR) V beta + cells. MRSA produced enterotoxins C and A and toxic shock syndrome toxin (TSST)-1, all of which are known to act as superantigens. From the above observations, we speculate that post-MRSA glomerulonephritis may be induced by superantigens causing production of high levels of cytokines, and polyclonal activation of IgG and IgA. The formation of ICs containing IgA and IgG in the circulation result in development of glomerulonephritis and vasculitis. Accordingly, microbial superantigens may play an important role in the pathogenesis of this unique syndrome of nephritis and vasculitis.

Src-family kinases, known to participate in signaling pathways of a variety of surface receptors, are localized to the cytoplasmic side of the plasma membrane through lipid modification. We show here that Lyn, a member of the Src-family kinases, is biosynthetically transported to the plasma membrane via the Golgi pool of caveolin along the secretory pathway. The trafficking of Lyn from the Golgi apparatus to the plasma membrane is inhibited by deletion of the kinase domain or Csk-induced “closed conformation” but not by kinase inactivation. Four residues (Asp346 and Glu353 on αE helix, and Asp498 and Asp499 on αI helix) present in the C-lobe of the kinase domain, which can be exposed to the molecular surface through an “open conformation,” are identified as being involved in export of Lyn from the Golgi apparatus toward the plasma membrane but not targeting to the Golgi apparatus. Thus, the kinase domain of Lyn plays a role in Lyn trafficking besides catalysis of substrate phosphorylation.

A rational method for constructing highly oriented films of purple membrane (PM) has been established by using two kinds of bispecific antibodies with different antigen-binding sites, one binding to a specific side of bacteriorhodopsin and the other to a phospholipid hapten. A hapten monolayer deposited on a metal electrode was treated with a bispecific antibody solution and incubated with a PM suspension to produce a highly oriented PM film, as confirmed by electron microscopy in which an immunogold labeling technique was used. This antibody-mediated PM monolayer was then used in the construction of a light-sensing photoelectric device. A comparison of the two incorporated PM monolayers showed that highly efficient photocurrents were produced by the PM monolayer whose unidirectionally oriented cytoplasmic surface faces the electrode.

Murine interleukin‐5 (IL‐5) is known to play an essential role in Ig production of B cells and proliferation and differentiation of eosinophils. Here, we have isolated cDNA clones encoding a murine IL‐5 receptor by expression screening of a library prepared from a murine IL‐5 dependent early B cell line. A cDNA library was expressed in COS7 cells and screened by panning with the use of anti‐IL‐5 receptor monoclonal antibodies. The deduced amino acid sequence analysis demonstrates that the receptor is a glycoprotein of 415 amino acids (Mr 45,284), including an N‐terminal hydrophobic region (17 amino acids), a glycosylated extracellular domain (322 amino acids), a single transmembrane segment (22 amino acids) and a cytoplasmic tail (54 amino acids). COS7 cells transfected with the cDNA expressed a 60 kd protein that bound IL‐5 with a single class of affinity (KD = 2–10 nM). FDC‐P1 cells transfected with the cDNA for murine IL‐5 receptor showed the expression of IL‐5 binding sites with both low (KD = 6 nM) and high affinity (KD = 30 pM) and acquired responsiveness to IL‐5 for proliferation, although parental FDC‐P1 cells did not show any detectable IL‐5 binding. In addition, several cDNA clones encoding soluble forms of the IL‐5 receptor were isolated. Northern blot analysis showed that two species of mRNAs (5.0 kb and 5.8 kb) were detected in cell lines that display binding sites for murine IL‐5. Homology search for the amino acid sequence of the IL‐5 receptor reveals that the IL‐5 receptor contains a common motif of a cytokine receptor family that is recently identified.