title: Amyloidogenic variant of apolipoprotein A-I elicits cellular stress by attenuating the protective activity of angiogenin.
abstract: Amyloidogenic 'gain-of-function' mutations in apolipoprotein A-I (ApoA-I) gene (APOA1) result in systemic amyloidosis characterized by aggregate deposition and eventually cell death. However, how amyloidogenic variants of ApoA-I induce cell death is unknown. Here we report that one of the mechanisms by which amyloidogenic ApoA-I induces cell death is through attenuating anti-stress activity of angiogenin (ANG), a homeostatic protein having both pro-growth and pro-survival functions. Under growth conditions, ANG is located in nucleolus where it promotes ribosomal RNA (rRNA) transcription thereby stimulating cell growth. In adverse conditions, ANG is relocated to cytoplasm to promote damage repairs and cell survival. We find that in cells overexpressing the L75P-APOA1 mutant ANG expression is decreased and normal cellular localization of ANG is altered in response to stress and growth signals. In particular, ANG does not relocate to cytoplasm under stress conditions but is rather retained in the nucleolus where it continues promoting rRNA transcription, thus imposing a ribotoxic effect while simultaneously compromising its pro-survival activity. Consistently, we also find that addition of exogenous ANG protects cells from L75P-ApoA-I-induced apoptosis.
authors.affiliation: 1] Department of Chemical Sciences, University of Naples Federico II, via Cinthia 4, Naples 80126, Italy [2] Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
authors.forename: R
authors.initials: R
authors.lastname: Del Giudice
authors.affiliation: 1] Department of Chemical Sciences, University of Naples Federico II, via Cinthia 4, Naples 80126, Italy [2] National Institute of Biostructures and Biosystems (INBB), Rome, Italy.
authors.forename: D M
authors.initials: DM
authors.lastname: Monti
authors.affiliation: Department of Biology, University of Naples Federico II, via Cinthia 4, Naples 80126, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Sarcinelli
authors.affiliation: 1] Department of Chemical Sciences, University of Naples Federico II, via Cinthia 4, Naples 80126, Italy [2] National Institute of Biostructures and Biosystems (INBB), Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Arciello
authors.affiliation: 1] Department of Chemical Sciences, University of Naples Federico II, via Cinthia 4, Naples 80126, Italy [2] National Institute of Biostructures and Biosystems (INBB), Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Piccoli
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
authors.forename: G-F
authors.initials: GF
authors.lastname: Hu
mesh_terms: D058227:Amyloidogenic Proteins / Q000235:genetics / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002466:Cell Nucleolus / Q000378:metabolism; D002470:Cell Survival; D014644:Genetic Variation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D021381:Protein Transport; D012335:RNA, Ribosomal / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C505693:APOA1 protein, human; D058227:Amyloidogenic Proteins; D016632:Apolipoprotein A-I; D012335:RNA, Ribosomal; C046366:angiogenin; D012259:Ribonuclease, Pancreatic