The hepatitis B virus-X protein (HBx) regulates fundamental aspects of mitochondrial physiology. We show that HBx down-regulates mitochondrial enzymes involved in electron transport in oxidative phosphorylation (complexes I, III, IV, and V) and sensitizes the mitochondrial membrane potential in a hepatoma cell line. HBx also increases the level of mitochondrial reactive oxygen species and lipid peroxide production. HBx does not activate apoptotic signaling, although it sensitizes hepatoma cells to apoptotic signaling, which is dependent on reactive oxygen species. Increased intrahepatic lipid peroxidation in HBx transgenic mice demonstrated that oxidative injury occurs as a direct result of HBx expression. Therefore, we conclude that mitochondrial dysfunction is a crucial pathophysiological factor in HBx-expressing hepatoma cells and provides an experimental rationale in the investigation of mitochondrial function in rapidly renewed tissues, as in hepatocellular carcinomas.

Background: TNF receptor-associated factor 2 (TRAF2) is a key adaptor molecule in the TNF receptor (TNFR) signaling pathway. Results: TRAF-interacting protein (TRIP) inhibits Lys63 -linked TRAF2 ubiquitination by blocking the binding of the cofactor sphingosine 1-phosphate (S1P) to the TRAF2 RING domain. Conclusion: TRIP negatively regulates the TRAF2 ubiquitin-dependent pathway by modulating the TRAF2-S1P interaction. Significance: TRIP is an important cellular regulator of the TNFR-mediated inflammatory response.

Abstract:We have isolated a cDNA clone from the nematode Caenorhabditis elegans that encodes a protein of greatest sequence similarity to muscarinic acetylcholine receptors. This gene codes for a polypeptide of 682 amino acids containing seven putative transmembrane domains. The amino acid identities, excluding a highly variable middle portion of the third intracellular loop, to the human m1-m5 receptors are 28 -34%. When this cloned receptor was coexpressed with a G protein-gated inwardly rectifying K ϩ channel (GIRK1) in Xenopus oocyte, acetylcholine was able to elicit the GIRK current. This acetylcholine-induced current was substantially inhibited by the muscarinic antagonist atropine in a reversible manner. However, another muscarinic agonist oxotremorine and antagonists scopolamine and pirenzepine had little or negligible effects on this receptor. Taken together, these results suggest that the cloned gene encodes a G protein-linked acetylcholine receptor that is most similar to but pharmacologically distinct from muscarinic acetylcholine receptors. Key Words: G proteinlinked acetylcholine receptor-Muscarinic acetylcholine receptor-Caenorhabditis elegans-G protein-gated inwardly rectifying K ϩ channel-Xenopus oocyte-Electrophysiology.

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Background: Genetic defects in the OSTM1 (osteopetrosis-associated transmembrane protein 1) gene cause autosomal recessive osteopetrosis. Results:The loss of the transmembrane domain in the OSTM1 gene produces a secreted form of truncated OSTM1 that inhibits osteoclast differentiation and survival. Conclusion: Extracellular secretion of a truncated OSTM1 is negatively involved in osteoclastogenesis. Significance: We identified a novel function for the secreted form of truncated OSTM1 in osteoclastogenesis.

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Highlights d ATAD5 and BRD4 are enriched on nascent DNA d A conserved region upstream of ATAD5 PCNA-unloading domain binds to BRD4 ET domain d Acetyl-histone-bound BRD4 inhibits PCNA unloading by ATAD5-RLC on nascent DNA

Poly(ADP‐ribose) polymerase 1 (PARP1) facilitates DNA damage response (DDR). While the Ewing's sarcoma breakpoint region 1 (EWS) protein fused to FLI1 triggers sarcoma formation, the physiological function of EWS is largely unknown. Here, we investigate the physiological role of EWS in regulating PARP1. We show that EWS is required for PARP1 dissociation from damaged DNA. Abnormal PARP1 accumulation caused by EWS inactivation leads to excessive Poly(ADP‐Ribosy)lation (PARylation) and triggers cell death in both in vitro and in vivo models. Consistent with previous work, the arginine‐glycine‐glycine (RGG) domain of EWS is essential for PAR chain interaction and PARP1 dissociation from damaged DNA. Ews and Parp1 double mutant mice do not show improved survival, but supplementation with nicotinamide mononucleotides extends Ews‐mutant pups’ survival, which might be due to compensatory activation of other PARP proteins. Consistently, PARP1 accumulates on chromatin in Ewing's sarcoma cells expressing an EWS fusion protein that cannot interact with PARP1, and tissues derived from Ewing's sarcoma patients show increased PARylation. Taken together, our data reveal that EWS is important for removing PARP1 from damaged chromatin.