Human mandibular shape is associated with masticatory muscle force

Understanding how and to what extent forces applied to the mandible by the masticatory muscles influence its form, is of considerable importance from clinical, anthropological and evolutionary perspectives. This study investigates these questions. Head CT scans of 382 adults were utilized to measure masseter and temporalis muscle cross-sectional areas (CSA) as a surrogate for muscle force, and 17 mandibular anthropometric measurements. Sixty-two mandibles of young individuals (20-40 years) whose scans were without artefacts (e.g., due to tooth filling) were segmented and landmarked for geometric morphometric analysis. The association between shape and muscle CSA (controlled for size) was assessed using two-block partial least squares analysis. Correlations were computed between mandibular variables and muscle CSAs (all controlled for size). A significant association was found between mandibular shape and muscle CSAs, i.e. larger CSAs are associated with a wider more trapezoidal ramus, more massive coronoid, more rectangular body and a more curved basal arch. Linear measurements yielded low correlations with muscle CSAs. In conclusion, this study demonstrates an association between mandibular muscle force and mandibular shape, which is not as readily identified from linear measurements. Retrodiction of masticatory muscle force and so of mandibular loading is therefore best based on overall mandibular shape

Regulation of Toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20

Toll-like receptor (TLR) signaling is linked to autophagy that facilitates elimination of intracellular pathogens. However, it is largely unknown whether autophagy controls TLR signaling. Here, we report that poly(I:C) stimulation induces selective autophagic degradation of the TLR adaptor molecule TRIF and the signaling molecule TRAF6, which is revealed by gene silencing of the ubiquitin-editing enzyme A20. This type of autophagy induced formation of autophagosomes and could be suppressed by an autophagy inhibitor and lysosomal inhibitors. However, this autophagy was not associated with canonical autophagic processes, including involvement of Beclin-1 and conversion of LC3-I to LC3-II. Through screening of TRIF-interacting ‘autophagy receptors’ in human cells, we identified that NDP52 mediated the selective autophagic degradation of TRIF and TRAF6 but not TRAF3. NDP52 was polyubiquitinated by TRAF6 and was involved in aggregation of TRAF6, which may result in the selective degradation. Intriguingly, only under the condition of A20 silencing, NDP52 could effectively suppress poly(I:C)-induced proinflammatory gene expression. Thus, this study clarifies a selective autophagic mechanism mediated by NDP52 that works downstream of TRIF–TRAF6. Furthermore, although A20 is known as a signaling fine-tuner to prevent excess TLR signaling, it paradoxically downregulates the fine-tuning effect of NDP52 on TLR signaling

EBV Tegument Protein BNRF1 Disrupts DAXX-ATRX to Activate Viral Early Gene Transcription

Productive infection by herpesviruses involve the disabling of host-cell intrinsic defenses by viral encoded tegument proteins. Epstein-Barr Virus (EBV) typically establishes a non-productive, latent infection and it remains unclear how it confronts the host-cell intrinsic defenses that restrict viral gene expression. Here, we show that the EBV major tegument protein BNRF1 targets host-cell intrinsic defense proteins and promotes viral early gene activation. Specifically, we demonstrate that BNRF1 interacts with the host nuclear protein Daxx at PML nuclear bodies (PML-NBs) and disrupts the formation of the Daxx-ATRX chromatin remodeling complex. We mapped the Daxx interaction domain on BNRF1, and show that this domain is important for supporting EBV primary infection. Through reverse transcription PCR and infection assays, we show that BNRF1 supports viral gene expression upon early infection, and that this function is dependent on the Daxx-interaction domain. Lastly, we show that knockdown of Daxx and ATRX induces reactivation of EBV from latently infected lymphoblastoid cell lines (LCLs), suggesting that Daxx and ATRX play a role in the regulation of viral chromatin. Taken together, our data demonstrate an important role of BNRF1 in supporting EBV early infection by interacting with Daxx and ATRX; and suggest that tegument disruption of PML-NB-associated antiviral resistances is a universal requirement for herpesvirus infection in the nucleus

A Role for Cytoplasmic PML in Cellular Resistance to Viral Infection

PML gene was discovered as a fusion partner with retinoic acid receptor (RAR) α in the t(15:17) chromosomal translocation associated with acute promyelocytic leukemia (APL). Nuclear PML protein has been implicated in cell growth, tumor suppression, apoptosis, transcriptional regulation, chromatin remodeling, DNA repair, and anti-viral defense. The localization pattern of promyelocytic leukemia (PML) protein is drastically altered during viral infection. This alteration is traditionally viewed as a viral strategy to promote viral replication. Although multiple PML splice variants exist, we demonstrate that the ratio of a subset of cytoplasmic PML isoforms lacking exons 5 & 6 is enriched in cells exposed to herpes simplex virus-1 (HSV-1). In particular, we demonstrate that a PML isoform lacking exons 5 & 6, called PML Ib, mediates the intrinsic cellular defense against HSV-1 via the cytoplasmic sequestration of the infected cell protein (ICP) 0 of HSV-1. The results herein highlight the importance of cytoplasmic PML and call for an alternative, although not necessarily exclusive, interpretation regarding the redistribution of PML that is seen in virally infected cells

Transcriptional Activation of the Adenoviral Genome Is Mediated by Capsid Protein VI

Gene expression of DNA viruses requires nuclear import of the viral genome. Human Adenoviruses (Ads), like most DNA viruses, encode factors within early transcription units promoting their own gene expression and counteracting cellular antiviral defense mechanisms. The cellular transcriptional repressor Daxx prevents viral gene expression through the assembly of repressive chromatin remodeling complexes targeting incoming viral genomes. However, it has remained unclear how initial transcriptional activation of the adenoviral genome is achieved. Here we show that Daxx mediated repression of the immediate early Ad E1A promoter is efficiently counteracted by the capsid protein VI. This requires a conserved PPxY motif in protein VI. Capsid proteins from other DNA viruses were also shown to activate the Ad E1A promoter independent of Ad gene expression and support virus replication. Our results show how Ad entry is connected to transcriptional activation of their genome in the nucleus. Our data further suggest a common principle for genome activation of DNA viruses by counteracting Daxx related repressive mechanisms through virion proteins

Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity

CLONING AND CHARACTERIZATION OF THE HUMAN GENE ENCODING ASPARTYL BETA-HYDROXYLASE

KORIOTH F, GIEFFERS C, Frey J. CLONING AND CHARACTERIZATION OF THE HUMAN GENE ENCODING ASPARTYL BETA-HYDROXYLASE. GENE. 1994;150(2):395-399.Sequence information for aspartyl beta-hydroxylase (AspH), which specifically hydroxylates one Asp or Asn residue in certain epidermal growth factor (EGF)-like domains oi a number of proteins, is so far only described for bovine species. We have isolated a 4.3-kb cDNA encoding the human AspH (hAspH) by immunoscreening of a human osteosarcoma (MG63) cDNA library in lambda ZAP with an antiserum raised against membrane fractions of these cells. Northern blot analyses revealed two transcripts with lengths of 2.6 and 4.3 kb. The deduced amino acid (aa) sequence of this cDNA encodes a protein of 757 aa (85 kDa). Comparison with the deduced bovine AspH (bAspH) aa sequence showed striking differences in the N-terminal portion of this protein. In vitro transcription and translation in the presence of canine pancreas microsomes yielded a 56-kDa protein. Western blot analyses of membrane fractions from MG63 cells with AspH-specific antibodies revealed a protein of the same M(r). These results suggest a posttranslational cleavage of the catalytic C terminus in the lumen of the endoplasmic reticulum

MOLECULAR CHARACTERIZATION OF NDP52, A NOVEL PROTEIN OF THE NUCLEAR DOMAIN-10, WHICH IS REDISTRIBUTED UPON VIRUS-INFECTION AND INTERFERON TREATMENT

KORIOTH F, GIEFFERS C, MAUL GG, FREY J. MOLECULAR CHARACTERIZATION OF NDP52, A NOVEL PROTEIN OF THE NUCLEAR DOMAIN-10, WHICH IS REDISTRIBUTED UPON VIRUS-INFECTION AND INTERFERON TREATMENT. JOURNAL OF CELL BIOLOGY. 1995;130(1):1-13

Mitofilin is a transmembrane protein of the inner mitochondrial membrane expressed as two isoforms

Gieffers C, Korioth F, Heimann P, Ungermann C, Frey J. Mitofilin is a transmembrane protein of the inner mitochondrial membrane expressed as two isoforms. EXPERIMENTAL CELL RESEARCH. 1997;232(2):395-399.Mitofilin, also known as heart muscle protein, is a recently identified mitochondrial protein. We have isolated two human cDNAs that encode different isoforms of mitofilin. Using reverse PCR, we provide evidence that both isoforms are derived by alternative splicing and encode two proteins of 88 and 90 kDa that are detected in immunoblot analyses with mitofilin-specific antibodies, Immunofluorescence microscopy, fractionating of human osteosarcoma cells, and protease protection experiments with isolated mitochondria and mitoplasts indicate that mitofilin is an integral membrane protein of the inner mitochondrial membrane. S-35-labeled mitofilin is transported into isolated yeast mitochondria in a reaction that depends on the membrane potential across the inner mitochondrial membrane (Delta Psi). During mitochondrial in vitro import, mitofilin is proteolytically processed to the mature protein that is also detected in cellular fractions, indicating that the amino-terminal leader sequence is removed, Sequence analysis and our re suits suggest that mitofilin is anchored in the inner mitochondrial membrane with an amino-terminal transmembrane domain, while the majority of the protein is extruding into the intermembrane space. (C) 1997 Academic Press

The nuclear domain 10 (ND10) is disrupted by the human cytomegalovirus gene product IE1

Korioth F, Maul GG, Plachter B, Stamminger T, Frey J. The nuclear domain 10 (ND10) is disrupted by the human cytomegalovirus gene product IE1. EXPERIMENTAL CELL RESEARCH. 1996;229(1):155-158.The nuclear domain 10 (ND10) is modified during the life cycle of a number of viruses. In this study we report the effect of infection with human cytomegalovirus (HCMV) on the ND10 proteins PML, Sp100, and NDP52. Immunofluorescence analyses revealed that 1-2 h after infection (p.i.) with HCMV the immediate early gene (IE) products IE1 and IE2 transiently colocalize with ND10 proteins. At 4 h p.i. the IE gene products were distributed throughout the nucleus, which was accompanied by a complete disruption of ND10, affecting all analyzed proteins. Transfection studies using different HCMV-cDNA expression plasmids revealed that the expression of IE1 alone was sufficient to induce this disruption. As reported for other ND10-modifying viral proteins, no direct interaction between IE1 and the analyzed ND10 proteins could be detected. The disruption of ND10 by HCMV IE1 is very similar to that described for HSV-1 ICP0. Although there is no sequence similarity between proteins, this observation might suggest similar functions in virus-host interactions. (C) 1996 Academic Press, Inc