Neprilysin 4, a novel endopeptidase from<i>Drosophila melanogaster</i>, displays distinct substrate specificities and exceptional solubility states

Meyer, Heiko; Panz, Mareike; Zmojdzian, Monika; Jagla, Krzysztof; Paululat, Achim

doi:10.1242/jeb.034272

Cited by 25 publications

(36 citation statements)

References 43 publications

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Section: Larval Expression Patterns Of Nep1-5supporting

confidence: 90%

“…The expression of Nep4 in third instar larvae is restricted to the central nervous system. Based on the size of the cells that are stained in the brain and ventral ganglia we identify the Nep4-expressing cells as glia ( Figure 4D), consistent with a previous report of colocalization of Nep4 with the glial marker Repo (Meyer et al 2009).Outside the CNS, Neps are expressed in the gut and the Malpighian tubules, as well as in developing wing, leg, and eye-antennal discs. More specifically Nep1 expression is detected in cells of the midgut (Figure 4E), wing disc (Figure 4I), and leg disc ( Figure 4J).…”

supporting

confidence: 89%

“…Nep4 RNA was detected as early as stage 12 in two patches of cells per hemisegment ( Figure 3A). These have been reported independently to correspond to muscle founder cells (Meyer et al 2009). In stage 13, Nep4 is expressed in two rows of cells that border the amnioserosa ( Figure 3B), which we identify as the pericardial cells.…”

Section: Expression Patterns Of Nep1-5mentioning

confidence: 68%

“…Neprilysinlike activity has been detected in extracts of larval imaginal discs and of neuronal membranes from larval and adult heads of Drosophila Wilson et al 2002). At least two Drosophila genes, Nep2 (Bland et al 2007) and Nep4 (Meyer et al 2009), are active proteases with specific substrate affinities that can be inhibited with the M13-specific peptidase inhibitors thiorphan and phosphoramidon. Nep2 has been shown to cleave locustatachykinin-1 (LomTK-1) and Drosophila tachykinins in vitro (Thomas et al 2005).…”

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confidence: 99%

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Neprilysins: An Evolutionarily Conserved Family of Metalloproteases That Play Important Roles in Reproduction in Drosophila

et al. 2014

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Members of the M13 class of metalloproteases have been implicated in diseases and in reproductive fitness. Nevertheless, their physiological role remains poorly understood. To obtain a tractable model with which to analyze this protein family's function, we characterized the gene family in Drosophila melanogaster and focused on reproductive phenotypes. The D. melanogaster genome contains 24 M13 class protease homologs, some of which are orthologs of human proteases, including neprilysin. Many are expressed in the reproductive tracts of either sex. Using RNAi we individually targeted the five Nep genes most closely related to vertebrate neprilysin, Nep1-5, to investigate their roles in reproduction. A reduction in Nep1, Nep2, or Nep4 expression in females reduced egg laying. Nep1 and Nep2 are required in the CNS and the spermathecae for wild-type fecundity. Females that are null for Nep2 also show defects as hosts of sperm competition as well as an increased rate of depletion for stored sperm. Furthermore, eggs laid by Nep2 mutant females are fertilized normally, but arrest early in embryonic development. In the male, only Nep1 was required to induce normal patterns of female egg laying. Reduction in the expression of Nep2-5 in the male did not cause any dramatic effects on reproductive fitness, which suggests that these genes are either nonessential for male fertility or perform redundant functions. Our results suggest that, consistent with the functions of neprilysins in mammals, these proteins are also required for reproduction in Drosophila, opening up this model system for further functional analysis of this protein class and their substrates. P ROTEASES play key roles in diverse physiological systems. One such family of metalloproteases, the M13 class of neutral endopeptidases, consists mainly of membranebound zinc proteases that are involved in the processing of neuropeptides and peptide hormones (reviewed in Turner et al. 2000;Turner et al. 2001;Bland et al. 2008). In mammals, seven members of this family have been identified, of which neprilysin (NEP) and endothelin converting enzyme (ECE) are the best studied. These proteins have been implicated in various diseases including cardiovascular disease (Segura and Ruilope 2011;Wick et al. 2011), Alzheimer's disease (Mulder et al. 2012;Klein et al. 2013), inflammation and inflammatory disorders (Wong et al. 2011), and cancer (Smollich et al. 2007;Maguer-Satta et al. 2011).In addition to their role in disease, NEPs are essential for development and reproduction in mammals. The mammalian Neprilysin-2, called NL1 in mice, is highly expressed in the testis. NL1-deficient males sire fewer pups, even though spermatogenesis appears to be unaffected (Carpentier et al. 2004). In females, NEP expression in the uterus is modulated by estrogen treatment in rats (Pinto et al. 1999) and during the estrogen/progesterone cycle in humans (Head et al. 1993). In female rats and mice, controlled degradation of tachykinins, particularly substance-P, by NEP in the uterus ...

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Section: Larval Expression Patterns Of Nep1-5supporting

confidence: 90%

supporting

confidence: 89%

Section: Expression Patterns Of Nep1-5mentioning

confidence: 68%

mentioning

confidence: 99%

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Neprilysins: An Evolutionarily Conserved Family of Metalloproteases That Play Important Roles in Reproduction in Drosophila

et al. 2014

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“…Nep1 is the fly ortholog of human neprilysin (hNEP) ). Catalytic activity has been demonstrated for two Drosophila neprilysins, Nep2 (Thomas et al, 2005;Bland et al, 2007) and Nep4 (Meyer et al, 2009). reference.…”

Section: Introductionmentioning

confidence: 99%

DrosophilaNeprilysins Are Involved in Middle-Term and Long-Term Memory

et al. 2016

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Neprilysins are type II metalloproteinases known to degrade and inactivate a number of small peptides. Neprilysins in particular are the major amyloid-␤ peptide-degrading enzymes. In mouse models of Alzheimer's disease, neprilysin overexpression improves learning and memory deficits, whereas neprilysin deficiency aggravates the behavioral phenotypes. However, whether these enzymes are involved in memory in nonpathological conditions is an open question. Drosophila melanogaster is a well suited model system with which to address this issue. Several memory phases have been characterized in this organism and the neuronal circuits involved are well described. The fly genome contains five neprilysin-encoding genes, four of which are expressed in the adult. Using conditional RNA interference, we show here that all four neprilysins are involved in middle-term and long-term memory. Strikingly, all four are required in a single pair of neurons, the dorsal paired medial (DPM) neurons that broadly innervate the mushroom bodies (MBs), the center of olfactory memory. Neprilysins are also required in the MB, reflecting the functional relationship between the DPM neurons and the MB, a circuit believed to stabilize memories. Together, our data establish a role for neprilysins in two specific memory phases and further show that DPM neurons play a critical role in the proper targeting of neuropeptides involved in these processes.

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Molecular characterization of western corn rootworm pyrethroid resistance

Souza

Siegfried

Meinke

et al. 2020

Pest Management Science

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BACKGROUND Western corn rootworm (WCR) pyrethroid resistance has been confirmed in the western US Corn Belt. Toxicological and biochemical studies indicated that multiple mechanisms of resistance might be involved in the resistance trait, such as enhanced metabolism and/or kdr target‐site mutation(s) in the voltage‐gated sodium channels. To characterize the mechanisms of WCR pyrethroid resistance at the molecular level, pairwise comparisons were made between RNA‐Seq data collected from pyrethroid‐resistant and ‐susceptible WCR populations. Gene expression levels and sodium channel sequences were evaluated. RESULTS Seven transcripts exhibited significantly different expression (q ≤ 0.05) when comparing field‐collected pyrethroid‐resistant (R‐Field) and ‐susceptible (S‐Field) WCR populations. Three of the differentially expressed transcripts were P450s overexpressed in R‐Field (9.2–26.2‐fold). A higher number (99) of differentially expressed transcripts was found when comparing laboratory‐derived pyrethroid‐resistant (R‐Lab) and ‐susceptible (S‐Lab) WCR populations. Eight of the significant transcripts were P450s overexpressed in R‐Lab (2.7–39.8‐fold). This study did not detect kdr mutations in pyrethroid‐resistant WCR populations. Other differentially expressed transcripts that may play a role in WCR pyrethroid resistance are discussed. CONCLUSION This study revealed that P450‐mediated metabolism is likely to be a major mechanism of WCR pyrethroid resistance, which could affect the efficacy of other insecticides sharing similar metabolic pathways. Additionally, results suggested that although laboratory selection of a pyrethroid‐resistant WCR population may help to characterize resistance mechanisms, a field‐selected population provided rare and perhaps major variants corresponding to the resistance trait.

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Neprilysin 4, a novel endopeptidase fromDrosophila melanogaster, displays distinct substrate specificities and exceptional solubility states

Abstract: SUMMARY Supplementary material available online at

Cited by 25 publications

References 43 publications

Neprilysins: An Evolutionarily Conserved Family of Metalloproteases That Play Important Roles in Reproduction in Drosophila

Neprilysins: An Evolutionarily Conserved Family of Metalloproteases That Play Important Roles in Reproduction in Drosophila

DrosophilaNeprilysins Are Involved in Middle-Term and Long-Term Memory

Molecular characterization of western corn rootworm pyrethroid resistance

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