Antiapoptotic protein Lifeguard is required for survival and maintenance of Purkinje and granular cells

Mendoza, Tatiana Hurtado de; Pérez-García, Carlos G.; Kroll, Todd T.; Hoong, Nien; O’Leary, Dennis D.M.; Verma, Inder M.

doi:10.1073/pnas.1114226108

Cited by 30 publications

(37 citation statements)

References 33 publications

(39 reference statements)

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“…Depletion of FAIM2/ LFG from neurons increases sensitivity to Fas-mediated apoptosis and developmental cell death, while overexpression of FAIM2/LFG was protective from effects of FasL-mediated death of neurons (Beier et al, 2005;Fernández et al, 2007;Hurtado de Mendoza et al, 2011). Although no role in neurite or axonal growth was detected for the overexpressed FAIM2/LFG proteins, these constructs did not contain the 39UTR that we have shown localizes NMP35 mRNA into neuronal processes based on primers and ESTs used for their cloning.…”

Section: Discussionmentioning

confidence: 99%

Axonal transport of neural membrane protein 35 mRNA increases axon growth

Merianda

Vuppalanchi

Yoo

et al. 2013

Journal of Cell Science

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SummaryMany neuronal mRNAs are transported from cell bodies into axons and dendrites. Localized translation of the mRNAs brings autonomy to these processes that can be vast distances from the cell body. For axons, these translational responses have been linked to growth and injury signaling, but there has been little information about local function of individual axonally synthesized proteins. In the present study, we show that axonal injury increases levels of the mRNA encoding neural membrane protein 35 (NMP35) in axons, with a commensurate decrease in the cell body levels of NMP35 mRNA. The 39 untranslated region (39UTR) of NMP35 is responsible for this localization into axons. Previous studies have shown that NMP35 protein supports cell survival by inhibiting Fas-ligand-mediated apoptosis; however, these investigations did not distinguish functions of the locally generated NMP35 protein. Using axonally targeted versus cell-body-restricted NMP35 constructs, we show that NMP35 supports axonal growth, and overexpression of an axonally targeted NMP35 mRNA is sufficient to increase axonal outgrowth.

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Section: Discussionmentioning

confidence: 99%

Axonal transport of neural membrane protein 35 mRNA increases axon growth

Merianda

Vuppalanchi

Yoo

et al. 2013

Journal of Cell Science

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“…Although its location in lipid rafts in the plasma membrane has been reported (18), other studies have described its presence at the Golgi (19). LFG expression is influenced by the PI3K/Akt pathway (20), and the down-regulation of this protein renders cerebellar granule neurons sensitive to Fas-induced apoptosis (21). LFG also has cytoprotective effects in models of ischemia (22).…”

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confidence: 99%

Lifeguard Inhibits Fas Ligand-mediated Endoplasmic Reticulum-Calcium Release Mandatory for Apoptosis in Type II Apoptotic Cells

Urresti

Ruiz‐Meana

Coccia

et al. 2016

Journal of Biological Chemistry

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Death receptors are members of the tumor necrosis factor receptor superfamily involved in the extrinsic apoptotic pathway. Lifeguard (LFG) is a death receptor antagonist mainly expressed in the nervous system that specifically blocks Fas ligand (FasL)-induced apoptosis. To investigate its mechanism of action, we studied its subcellular localization and its interaction with members of the Bcl-2 family proteins. We performed an analysis of LFG subcellular localization in murine cortical neurons and found that LFG localizes mainly to the ER and Golgi. We confirmed these results with subcellular fractionation experiments. Moreover, we show by coimmunoprecipitation experiments that LFG interacts with Bcl-X L and Bcl-2, but not with Bax or Bak, and this interaction likely occurs in the endoplasmic reticulum. We further investigated the relationship between LFG and Bcl-X L in the inhibition of apoptosis and found that LFG protects only type II apoptotic cells from FasLinduced death in a Bcl-X L dependent manner. The observation that LFG itself is not located in mitochondria raises the question as to whether LFG in the ER participates in FasL-induced death. Indeed, we investigated the degree of calcium mobilization after FasL stimulation and found that LFG inhibits calcium release from the ER, a process that correlates with LFG blockage of cytochrome c release to the cytosol and caspase activation. On the basis of our observations, we propose that there is a required step in the induction of type II apoptotic cell death that involves calcium mobilization from the ER and that this step is modulated by LFG.

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“…The "healthspan" of these flies was highly compromised as determined by their shortened lifespan and precocious loss in locomotor function. LFG is able to block FasL-induced cell death and has been demonstrated to be neuroprotective (Schweitzer et al, 1998;Fernández et al, 2007;Hurtado de Mendoza et al, 2011;Reich et al, 2011), is highly expressed in neurons, and its loss-of-function induces cell death. The profound loss in climbing ability that results from knockdown of CG3814/LFG in Drosophila neurons appears to be the result of neuronal loss, since compared to control flies at around the same age and at the same time point, there is a significant difference in climbing abilities.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of the putative Lifeguard homologue CG3814 in neurons of Drosophila melanogaster

M’Angale

Staveley

2016

Genet. Mol. Res.

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ABSTRACT.Lifeguard is an integral transmembrane protein that modulates FasL-mediated apoptosis by interfering with the activation of caspase 8. It is evolutionarily conserved, with homologues present in plants, nematodes, zebra fish, frog, chicken, mouse, monkey, and human. The Lifeguard homologue in Drosophila, CG3814, contains the Bax inhibitor-1 family motif of unknown function. Downregulation of Lifeguard disrupts cellular homeostasis and disease by sensitizing neurons to FasL-mediated apoptosis. We used bioinformatic analyses to identify CG3814, a putative homologue of Lifeguard, and knocked down CG3814/LFG expression under the control of the Dopa decarboxylase (Ddc-Gal4) transgene in Drosophila melanogaster neurons to investigate whether it possesses neuroprotective activity. Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons resulted in a shortened lifespan and impaired locomotor ability, phenotypes that are strongly associated with the degeneration and loss of dopaminergic neurons. Lifeguard interacts with anti-apoptotic Bcl-2 proteins and possibly pro-apoptotic proteins to exert its neuroprotective function. The co-expression of Buffy, the sole anti-apoptotic Bcl-2 gene family member in Drosophila, and CG3814/LFG by stable inducible RNA interference, suppresses the shortened lifespan and the premature agedependent loss in climbing ability. Suppression of CG3814/LFG in the Drosophila eye reduces the number of ommatidia and increases disruption of the ommatidial array. Overexpression of Buffy, along with the knockdown of CG3814/LFG, counteracts the eye phenotypes. Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons in Drosophila diminishes its neuroprotective ability and results in a shortened lifespan and loss of climbing ability, phenotypes that are improved upon overexpression of the pro-survival Buffy.

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Antiapoptotic protein Lifeguard is required for survival and maintenance of Purkinje and granular cells

Cited by 30 publications

References 33 publications

Axonal transport of neural membrane protein 35 mRNA increases axon growth

Axonal transport of neural membrane protein 35 mRNA increases axon growth

Lifeguard Inhibits Fas Ligand-mediated Endoplasmic Reticulum-Calcium Release Mandatory for Apoptosis in Type II Apoptotic Cells

Knockdown of the putative Lifeguard homologue CG3814 in neurons of Drosophila melanogaster

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