Grasshopper Lazarillo, a GPI-anchored Lipocalin, increases Drosophila longevity and stress resistance, and functionally replaces its secreted homolog NLaz

Ruiz, Mario; Wicker-Thomas, Claude; Sánchez, Diego; Ganfornina, Marı́a D.

doi:10.1016/j.ibmb.2012.07.005

Cited by 22 publications

(29 citation statements)

References 58 publications

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“…S2 D , E ), which is unique to NLaz within the lipocalin family (51), as a different control for the NLaz L130R binding pocket mutant. This C‐terminal tail is similar in size to the glycosylphosphatidylinositol (GPI)‐anchoring signal peptide present in the lipocalin Lazarillo of grasshoppers and other insects (22, 52) but shows a quite different amino acid composition.…”

Section: Resultsmentioning

confidence: 97%

“…S2 cells seeded at a density of 2 × 10 6 /ml were treated with H 2 O 2 (Calbiochem, Billerica, MA, USA) as an oxidant agent in the presence of pure NLaz WT , NLaz L130R (see below) or a control protein (trypsin inhibitor from soybean; Sigma, St. Louis, MO, USA), as described previously (22). Viability was scored in quadruplicate wells with ≥2 measurements in each culture well.…”

Section: Methodsmentioning

confidence: 99%

“…NLaz is induced under the control of the stress‐responsive Jun‐N‐terminal kinase (JNK) pathway and is able to negatively regulate the insulin/insulin‐like growth factor signaling (IIS) pathway (16, 21). NLaz expression increases stress resistance and longevity, but also serves other apparently unrelated functions by regulating fecundity, food intake, and locomotor and courtship behaviors (18, 22). The molecular mechanism by which NLaz is able to perform these varied functions has not been elucidated yet, although general proposals of lipid transport or interaction with cellular lipid membrane surfaces have been laid out (23, 24).…”

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confidence: 99%

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Ligand binding‐dependent functions of the lipocalin NLaz: anin vivostudy inDrosophila

et al. 2013

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Lipocalins are small extracellular proteins mostly described as lipid carriers. The Drosophila lipocalin NLaz (neural Lazarillo) modulates the IIS pathway and regulates longevity, stress resistance, and behavior. Here, we test whether a native hydrophobic pocket structure is required for NLaz to perform its functions. We use a point mutation altering the binding pocket (NLaz(L130R)) and control mutations outside NLaz binding pocket. Tryptophan fluorescence titration reveals that NLaz(L130R) loses its ability to bind ergosterol and the pheromone 7(z)-tricosene but retains retinoic acid binding. Using site-directed transgenesis in Drosophila, we test the functionality of the ligand binding-altered lipocalin at the organism level. NLaz-dependent life span reduction, oxidative stress and starvation sensitivity, aging markers accumulation, and deficient courtship are rescued by overexpression of NLaz(WT), but not of NLaz(L130R). Transcriptional responses to aging and oxidative stress show a large set of age-responsive genes dependent on the integrity of NLaz binding pocket. Inhibition of IIS activity and modulation of oxidative stress and infection-responsive genes are binding pocket-dependent processes. Control of energy metabolites on starvation appears to be, however, insensitive to the modification of the NLaz binding pocket.

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Section: Resultsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Ligand binding‐dependent functions of the lipocalin NLaz: anin vivostudy inDrosophila

et al. 2013

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“…Second, an increase in both life span and stress resistance has also been observed as a result of overexpression of Lazarillo, the grasshopper ortholog of ApoD, in Drosophila. Moreover, Lazarillo has been demonstrated to functionally restore loss of Drosophila NLaz by rescuing stress resistance in a neuron-specific manner (Ruiz et al., 2012). Intriguingly, overexpression of human ApoD in Drosophila led to a reduction in age-associated lipid peroxidation, concomitant with an increase in stress resistance and longevity (Muffat et al., 2008).…”

Section: Apod In the Aging Brainmentioning

confidence: 99%

Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain

Dassati

Waldner

Schweigreiter

2014

Neurobiology of Aging

128

109

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Apolipoprotein D (ApoD) is an ancient member of the lipocalin family with a high degree of sequence conservation from insects to mammals. It is not structurally related to other major apolipoproteins and has been known as a small, soluble carrier protein of lipophilic molecules that is mostly expressed in neurons and glial cells within the central and peripheral nervous system. Recent data indicate that ApoD not only supplies cells with lipophilic molecules, but also controls the fate of these ligands by modulating their stability and oxidation status. Of particular interest is the binding of ApoD to arachidonic acid and its derivatives, which play a central role in healthy brain function. ApoD has been shown to act as a catalyst in the reduction of peroxidized eicosanoids and to attenuate lipid peroxidation in the brain. Manipulating its expression level in fruit flies and mice has demonstrated that ApoD has a favorable effect on both stress resistance and life span. The APOD gene is the gene that is upregulated the most in the aging human brain. Furthermore, ApoD levels in the nervous system are elevated in a large number of neurologic disorders including Alzheimer's disease, schizophrenia, and stroke. There is increasing evidence for a prominent neuroprotective role of ApoD because of its antioxidant and anti-inflammatory activity. ApoD emerges as an evolutionarily conserved anti-stress protein that is induced by oxidative stress and inflammation and may prove to be an effective therapeutic agent against a variety of neuropathologies, and even against aging.

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“…Moreover, the expression levels of invertebrate ApoD homologues have been shown to modulate longevity (Hull-Thompson et al, 2009;Ruiz et al, 2011Ruiz et al, , 2012Ruiz et al, , 2014Sanchez et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex

Sánchez

Bajo‐Grañeras

Caño-Espinel

et al. 2015

Experimental Gerontology

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Grasshopper Lazarillo, a GPI-anchored Lipocalin, increases Drosophila longevity and stress resistance, and functionally replaces its secreted homolog NLaz

Cited by 22 publications

References 58 publications

Ligand binding‐dependent functions of the lipocalin NLaz: anin vivostudy inDrosophila

Ligand binding‐dependent functions of the lipocalin NLaz: anin vivostudy inDrosophila

Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain

Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex

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