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VCP (VCP/p97) is a ubiquitously expressed member of the AAA(+)-ATPase family of chaperone-like proteins that regulates numerous cellular processes including chromatin decondensation, homotypic membrane fusion and ubiquitin-dependent protein degradation by the proteasome. Mutations in VCP cause a multisystem degenerative disease consisting of inclusion body myopathy, Paget disease of bone, and frontotemporal dementia (IBMPFD). Here we show that VCP is essential for autophagosome maturation. We generated cells stably expressing dual-tagged LC3 (mCherry-EGFP-LC3) which permit monitoring of autophagosome maturation. We determined that VCP deficiency by RNAi-mediated knockdown or overexpression of dominant-negative VCP results in significant accumulation of immature autophagic vesicles, some of which are abnormally large, acidified and exhibit cathepsin B activity. Furthermore, expression of disease-associated VCP mutants (R155H and A232E) also causes this autophagy defect. VCP was found to be essential to autophagosome maturation under basal conditions and in cells challenged by proteasome inhibition, but not in cells challenged by starvation, suggesting that VCP might be selectively required for autophagic degradation of ubiquitinated substrates. Indeed, a high percentage of the accumulated autophagic vesicles contain ubiquitin-positive contents, a feature that is not observed in autophagic vesicles that accumulate following starvation or treatment with Bafilomycin A. Finally, we show accumulation of numerous, large LAMP-1 and LAMP-2-positive vacuoles and accumulation of LC3-II in myoblasts derived from patients with IBMPFD. We conclude that VCP is essential for maturation of ubiquitin-containing autophagosomes and that defect in this function may contribute to IBMPFD pathogenesis.

The essential branched‐chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence‐associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation‐related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age‐related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age‐related and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Author(s): Udai Bhan Pandey [1]; Zhiping Nie [1]; Yakup Batlevi [2]; Brett A. McCray [1]; Gillian P. Ritson [1]; Natalia B. Nedelsky [1]; Stephanie L. Schwartz [1]; Nicholas A. DiProspero [...]

Author(s): Charlotte Hubbert [1]; Amaris Guardiola [1]; Rong Shao [1, 3]; Yoshiharu Kawaguchi [2, 3]; Akihiro Ito [1]; Andrew Nixon [1]; Minoru Yoshida [2]; Xiao-Fan Wang [1]; Tso-Pang Yao (corresponding [...]

Research has been conducted on the CREB- binding protein (CBP). Results indicate that CBP has tumor-suppressor activity.

Gene expression and cell-differentiation are regulated by factors including the transcriptional co-activators p300 and CBP (cAMP-response-element-binding protein (CREB)-binding protein). Both proteins, which have basic histone-acetlytransferase activity, could mediate chromatin to aid transcription and are also implicated in growth control pathways. New research investigates the functional differences between p300 and CBP in vivo. Their roles during retinoic-acid-induced differentiation of F9 cells are examined. It is concluded that p300 and CBVP, although similar, have distinctly different functions in cell differentiation.

Laboratory mice that do not have the functional p300 gene were studied to determine the impact of the genetic defect on embryonic development, specifically neurulation, cell proliferation and heart development. Results revealed proliferation defects in the said embryos. Embryonic lethality was also observed among p300 heterozygotes. These findings indicated that mammalian cell proliferation and development requires a coactivator endowed with histone acetyltransferase activity.