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Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here, we define a molecular pathway through which recombinant IL-1 receptor antagonist (IL1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted [H.sub.2][O.sub.2]-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activated NADPH oxidase 4 independent of the IL- 1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL- 1R1dependent antiinflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease., Introduction The lung is equipped with a robust proteostasis network for handling protein folding, misfolding, unfolding, and degradation in response to mechanical and environmental stress (1). Consistent with the emerging [...]

Liver regeneration represents an outstanding tool to study not only proliferation, but also other important processes such as inflammation, regenerative response or stem cell biology. Several novel genes have been identified as being involved in the proliferation of residual hepatocytes. One of them, HOPS/TMUB1, is proving to be a significant player in the control of proliferation, both contributing to genomic stability and as a partner of essential molecules. HOPS is an ubiquitin‐like protein, shuttling from nucleus to cytoplasm, and it is engaged in a number of biological and physiopathological functions. HOPS overexpression in tumour cell lines strongly reduces proliferation, arresting cell cycle in G0/G1. HOPS is involved in centrosome assembly and maintenance, and its knockdown causes genomic instability. Moreover, a direct interaction of HOPS with nucleophosmin (NPM) and p19Arf has been established, resulting in proper control of p19Arf stability and localization. These data indicate that HOPS acts as a functional bridge in the interaction between NPM and p19Arf, providing new mechanistic insight into how NPM and p19Arf will oppose cell proliferation. HOPS exerts a control in p53 stability, directing p53 mitochondrial apoptosis and cytoplasmic localization. HOPS plays a direct role as novel post‐translational modifier of p53, much like SUMO or NEDD. HOPS is overexpressed in a high number of human tumours in patients affected by large intestinal, CNS, liver and oesophageal tumours. This review highlights HOPS involvement in distinct cellular functions, establishing its role as a key player in cell biology and pathology in a broader context. [ABSTRACT FROM AUTHOR]

Apoptotic signalling by p53 occurs at both transcriptional and non‐transcriptional levels, as p53 may act as a direct apoptogenic stimulus via activation of the intrinsic mitochondrial pathway. HOPS is a highly conserved, ubiquitously expressed shuttling protein with an ubiquitin‐like domain. We generated Hops−/− mice and observed that they are viable with no apparent phenotypic defects. However, when treated with chemotherapeutic agents, Hops−/− mice display a significant reduction in apoptosis, suggesting an impaired ability to respond to genotoxic stressors. We show that HOPS acts as a regulator of cytoplasmic p53 levels and function. By binding p53, HOPS inhibits p53 proteasomal degradation and favours p53 recruitment to mitochondria and apoptosis induction. By interfering with importin α, HOPS further increases p53 cytoplasmic levels. Thus, HOPS promotes the p53‐dependent mitochondrial apoptosis pathway by preserving cytoplasmic p53 from both degradation and nuclear uptake. Synopsis: Cytoplasmic p53 has important functions in apoptosis and autophagy. HOPS retains and stabilizes p53 in the cytoplasm and thereby promotes p53‐dependent mitochondrial apoptosis. Hops−/− mice are more resistant to DNA damage‐induced apoptosis.HOPS interacts with p53 and prevents its ubiquitylation and proteasomal degradation.HOPS promotes the mitochondrial accumulation of p53, which is a crucial step for apoptosis induction.HOPS retains p53 in the cytoplasm by competing with importin α‐mediated nuclear translocation. [ABSTRACT FROM AUTHOR]

Abstract: 3β-hydroxysterol Δ14-reductase operates during the conversion of lanosterol to cholesterol in mammalian cells. Besides the endoplasmic reticulum 3β-hydroxysterol Δ14-reductase (C14SR) encoded by TM7SF2 gene, the lamin B receptor (LBR) of the inner nuclear membrane possesses 3β-hydroxysterol Δ14-reductase activity, based on its ability to complement C14SR-defective yeast strains. LBR was indicated as the primary 3β-hydroxysterol Δ14-reductase in human cholesterol biosynthesis, since mutations in LBR gene were found in Greenberg skeletal dysplasia, characterized by accumulation of Δ14-unsaturated sterols. This study addresses the issue of C14SR and LBR role in cholesterol biosynthesis. Both human C14SR and LBR expressed in COS-1 cells exhibit 3β-hydroxysterol Δ14-reductase activity in vitro. TM7SF2 mRNA and C14SR protein expression in HepG2 cells grown in delipidated serum (LPDS) plus lovastatin (sterol starvation) were 4- and 8-fold higher, respectively, than in LPDS plus 25-hydroxycholesterol (sterol feeding), resulting in 4-fold higher 3β-hydroxysterol Δ14-reductase activity. No variations in LBR mRNA and protein levels were detected in the same conditions. The induction of TM7SF2 gene expression is turned-on by promoter activation in response to low cell sterol levels and is mediated by SREBP-2. The results suggest a primary role of C14SR in human cholesterol biosynthesis, whereas LBR role in the pathway remains unclear. [Copyright &y& Elsevier]

3Beta-hydroxysterol Delta(14)-reductase operates during the conversion of lanosterol to cholesterol in mammalian cells. Besides the endoplasmic reticulum 3beta-hydroxysterol Delta(14)-reductase (C14SR) encoded by TM7SF2 gene, the lamin B receptor (LBR) of the inner nuclear membrane possesses 3beta-hydroxysterol Delta(14)-reductase activity, based on its ability to complement C14SR-defective yeast strains. LBR was indicated as the primary 3beta-hydroxysterol Delta(14)-reductase in human cholesterol biosynthesis, since mutations in LBR gene were found in Greenberg skeletal dysplasia, characterized by accumulation of Delta(14)-unsaturated sterols. This study addresses the issue of C14SR and LBR role in cholesterol biosynthesis. Both human C14SR and LBR expressed in COS-1 cells exhibit 3beta-hydroxysterol Delta(14)-reductase activity in vitro. TM7SF2 mRNA and C14SR protein expression in HepG2 cells grown in delipidated serum (LPDS) plus lovastatin (sterol starvation) were 4- and 8-fold higher, respectively, than in LPDS plus 25-hydroxycholesterol (sterol feeding), resulting in 4-fold higher 3beta-hydroxysterol Delta(14)-reductase activity. No variations in LBR mRNA and protein levels were detected in the same conditions. The induction of TM7SF2 gene expression is turned-on by promoter activation in response to low cell sterol levels and is mediated by SREBP-2. The results suggest a primary role of C14SR in human cholesterol biosynthesis, whereas LBR role in the pathway remains unclear.

The liver has the ability to autonomously regulate growth and mass. Following partial hepatectomy, hormones, growth factors, cytokines and their coupled signal transduction pathways have been implicated in hepatocyte proliferation. To understand the mechanisms responsible for the proliferative response, we studied liver regeneration by characterization of novel genes that are activated in residual hepatocytes. A regenerating liver cDNA library screening was performed with cDNA-subtracted probes derived from regenerating and normal liver. Here, we describe the biology of Hops (for hepatocyte odd protein shuttling). HOPS is a novel shuttling protein that contains an ubiquitin-like domain, a putative NES and a proline-rich region. HOPS is rapidly exported from the nucleus and is overexpressed during liver regeneration. Evidence shows that cAMP governs HOPS export in hepatocytes of normal and regenerating liver and is mediated via CRM-1. We demonstrate that HOPS binds to elongation factor eEF-1A and interferes in protein synthesis. HOPS overexpression in H-35-hepatoma and 3T3-NIH cells strongly reduces proliferation.