Ambra1 regulates autophagy and development of the nervous system

By G. Fimia, Anastassia Stoykova, A. Romagnoli, Luigi Giunta, S. Bartolomeo, R. Nardacci, Marco Corazzari, C. Fuoco, A. Ucar, P. Schwartz and 4 more. Nature, 2007

1,046 citations recorded by the source corpus.

Autophagy is a self-degradative process involved both in basal turnover of cellular components and in response to nutrient starvation or organelle damage in a wide range of eukaryotes. During autophagy, portions of the cytoplasm are sequestered by double-membraned vesicles called autophagosomes, and are degraded after fusion with lysosomes for subsequent recycling. In vertebrates, this process acts as a pro-survival or pro-death mechanism in different physiological and pathological conditions, such as neurodegeneration and cancer; however, the roles of autophagy during embryonic development are still largely uncharacterized. Beclin1 (Becn1; coiled-coil, myosin-like BCL2-interacting protein) is a principal regulator in autophagosome formation, and its deficiency results in early embryonic lethality. Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy, as revealed by its overexpression and by RNA interference experiments in vitro. Notably, Ambra1 functional deficiency in mouse embryos leads to severe neural tube defects associated with autophagy impairment, accumulation of ubiquitinated proteins, unbalanced cell proliferation and excessive apoptotic cell death. In addition to identifying a new and essential element regulating the autophagy programme, our results provide in vivo evidence supporting the existence of a complex interplay between autophagy, cell growth and cell death required for neural development in mammals.

Subfields: Epidemiology, Immunology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/94ac37e709162f8b38fdf2b7f3b7deaae2ab6faf

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Citations in the corpus

The regulation of autophagy – unanswered questions (2011, background): “Atg14L (yeast Atg14-like) (Matsunaga et al., 2009; Zhong et al., 2009), activating molecule in beclin-1-regulated autophagy (AMBRA1) (Di Bartolomeo et al., 2010; Fimia et al., 2007), UV radiation resistance-associated gene (UVRAG) protein (Liang et al., 2008) and Bax-interacting factor 1 (Bif1) (Tak”
The Beclin 1 network regulates autophagy and apoptosis (2011, neutral): “Ambra1 has a role in the development of the nervous system.(45) Ambra1 functional deficiency in mouse embryos leads to severe neural tube defects associated with autophagy impairment, accumulation of ubiquitinated proteins, unbalanced cell proliferation, and excessive apoptotic cell death.”
Molecular characterization of LC3-associated phagocytosis (LAP) reveals distinct roles for Rubicon, NOX2, and autophagy proteins (2015, neutral): “Canonical autophagy requires ULK1-dependent release of a Beclin1-activating cofactor, Ambra1, from the dynein motor complex 23 , and the function of WIPI2 (ref.”
Mitochondria and Mitophagy: The Yin and Yang of Cell Death Control (2012, background): “In contrast, AMBRA1 stimulates new phagophore formation.(52) Thus, we believe that the 2 mechanisms have complimentary effects to allow for efficient mitophagy; AMBRA1 induces the formation of new phagophores at the mitochondria, which, after incorporation of LC3, may be tethered to ubiquitinated mi”
Autophagy-deficient mice develop multiple liver tumors. (2011, background): “Several Beclin 1-interacting proteins—including Ambra 1 (Fimia et al. 2007), Bif-1 (Takahashi et al. 2007), and UVRAG (Liang et al. 2006)— were also shown to have tumor-suppressive or anti-proliferation effects.”