Bphs controls Bordetella pertussis toxin (PTX)-induced vasoactive amine sensitization elicited by histamine (VAASH) and has an established role in autoimmunity. We report that congenic mapping links Bphs to the histamine H1 receptor gene (Hrh1/H1R) and that H1R differs at three amino acid residues in VAASH-susceptible and -resistant mice. Hrh1-/- mice are protected from VAASH, which can be restored by genetic complementation with a susceptible Bphs/Hrh1 allele, and experimental allergic encephalomyelitis and autoimmune orchitis due to immune deviation. Thus, natural alleles of Hrh1 control both the autoimmune T cell and vascular responses regulated by histamine after PTX sensitization.

Human papillomavirus (HPV) E6 oncoprotein targets certain tumor suppressors such as MAGI-1 and SAP97/ hDlg for degradation. A short peptide at the C terminus of E6 interacts specifically with the PDZ domains of these tumor suppressors, which is a property unique to high-risk HPVs that are associated with cervical cancer. The detailed recognition mechanisms between HPV E6 and PDZ proteins are unclear. To understand the specific binding of cellular PDZ substrates by HPV E6, we have solved the crystal structures of the complexes containing a peptide from HPV18 E6 bound to three PDZ domains from MAGI-1 and SAP97/Dlg. The complex crystal structures reveal novel features of PDZ peptide recognition that explain why high-risk HPV E6 can specifically target these cellular tumor suppressors for destruction. Moreover, a new peptide-binding loop on these PDZs is identified as interacting with the E6 peptide. Furthermore, we have identified an arginine residue, unique to high-risk HPV E6 but outside the canonical core PDZ recognition motif, that plays an important role in the binding of the PDZs of both MAGI-I and SAP97/Dlg, the mutation of which abolishes E6's ability to degrade the two proteins. Finally, we have identified a dimer form of MAGI-1 PDZ domain 1 in the cocrystal structure with E6 peptide, which may have functional relevance for MAGI-1 activity. In addition to its novel insights into the biochemistry of PDZ interactions, this study is important for understanding HPV-induced oncogenesis; this could provide a basis for developing antiviral and anticancer compounds.Human papillomaviruses (HPVs) are small double-stranded DNA tumor viruses that induce hyperproliferative lesions in epithelial tissues (28). A subset of HPV types that act as the etiological agent of cervical cancers are called "high-risk" types; these include HPV16, HPV18, HPV31, and HPV45 among others (26,27,29,45). The oncogenic potential of the high-risk types is dependent on the cooperative action of the two early viral gene products, E6 and E7, which bind and alter the activity of cell cycle regulatory proteins.The targeting of p53 for degradation by E6 has extensively been studied, and this is an important feature for the oncogenic activity of the high-risk papillomaviruses that cause cancer (19,36,37). However, a large amount of evidence suggests the existence of p53-independent functions of E6 that are also necessary and important for transformation. Support for this idea comes from the observation that the transformation of cells or the induction of epithelial hyperproliferation in transgenic animals by E6 does not always correlate with its ability to degrade p53 (22,33).Numerous cellular proteins have been identified as targets of HPV E6 in cell transformation. These proteins are involved in a variety of cellular processes, such as calcium signaling (4), cell adhesion (41), transcriptional control (5), DNA synthesis (25), apoptosis (8), cell cycle control (10), DNA repair (20), and small G-protein signaling (11). One group of these targets of...

BackgroundThe phylogeography of the Y chromosome in Asia previously suggested that modern humans of African origin initially settled in mainland southern East Asia, and about 25,000–30,000 years ago, migrated northward, spreading throughout East Asia. However, the fragmented distribution of one East Asian specific Y chromosome lineage (D-M174), which is found at high frequencies only in Tibet, Japan and the Andaman Islands, is inconsistent with this scenario.ResultsIn this study, we collected more than 5,000 male samples from 73 East Asian populations and reconstructed the phylogeography of the D-M174 lineage. Our results suggest that D-M174 represents an extremely ancient lineage of modern humans in East Asia, and a deep divergence was observed between northern and southern populations.ConclusionWe proposed that D-M174 has a southern origin and its northward expansion occurred about 60,000 years ago, predating the northward migration of other major East Asian lineages. The Neolithic expansion of Han culture and the last glacial maximum are likely the key factors leading to the current relic distribution of D-M174 in East Asia. The Tibetan and Japanese populations are the admixture of two ancient populations represented by two major East Asian specific Y chromosome lineages, the O and D haplogroups.