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Pelle Modulates dFoxO-Mediated Cell Death in Drosophila.

Wu C, Chen Y, Wang F, Chen C, Zhang S, Li C, Li W, Wu S, Xue L - PLoS Genet. (2015)

Bottom Line: Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals.Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly.This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.

ABSTRACT
Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals. Recent studies also suggest a critical role of IRAKs in tumor development, though the underlying mechanism remains elusive. Pelle is the sole Drosophila IRAK homolog implicated in the conserved Toll pathway that regulates Dorsal/Ventral patterning, innate immune response, muscle development and axon guidance. Here we report a novel function of pll in modulating apoptotic cell death, which is independent of the Toll pathway. We found that loss of pll results in reduced size in wing tissue, which is caused by a reduction in cell number but not cell size. Depletion of pll up-regulates the transcription of pro-apoptotic genes, and triggers caspase activation and cell death. The transcription factor dFoxO is required for loss-of-pll induced cell death. Furthermore, loss of pll activates dFoxO, promotes its translocation from cytoplasm to nucleus, and up-regulates the transcription of its target gene Thor/4E-BP. Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly. This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

dFoxO is required for loss-of-pll induced bristle phenotype on notum.(A-G) Light micrographs showing bristles on the adult notum. Compared with the pnr-Gal4 control (A), RNAi-mediated depletion of pll in notum resulted in reduced bristle number (B), which was suppressed by knocking-down dFoxO (D), deleting one or both copies of endogenous dFoxO (E and F), or expressing Pll (G), but not by expressing a GFP RNAi that served as a negative control (C). The lower panels show high magnification view of the boxed areas in upper panels. (H) Quantification of bristles number in the boxed areas from A-G. One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001, ** P<0.01). ns stands for not significant. Detailed genotypes: (A) pnr-Gal4/+ (B) UAS-pll-IRV2889/+; pnr-Gal4/+ (C) UAS-pll-IRV2889/+; pnr-Gal4/UAS-GFP-IR (D) UAS-pll-IRV2889/+; pnr-Gal4/UAS-dFoxO-IR (E) UAS-pll-IRV2889/+; pnr-Gal4/dFoxOΔ94 (F) UAS-pll-IRV2889/+; pnr-Gal4 dFoxOΔ94/dFoxOΔ94 (G) UAS-pll-IRV2889/+; pnr-Gal4/UAS-Pll.
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pgen.1005589.g008: dFoxO is required for loss-of-pll induced bristle phenotype on notum.(A-G) Light micrographs showing bristles on the adult notum. Compared with the pnr-Gal4 control (A), RNAi-mediated depletion of pll in notum resulted in reduced bristle number (B), which was suppressed by knocking-down dFoxO (D), deleting one or both copies of endogenous dFoxO (E and F), or expressing Pll (G), but not by expressing a GFP RNAi that served as a negative control (C). The lower panels show high magnification view of the boxed areas in upper panels. (H) Quantification of bristles number in the boxed areas from A-G. One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001, ** P<0.01). ns stands for not significant. Detailed genotypes: (A) pnr-Gal4/+ (B) UAS-pll-IRV2889/+; pnr-Gal4/+ (C) UAS-pll-IRV2889/+; pnr-Gal4/UAS-GFP-IR (D) UAS-pll-IRV2889/+; pnr-Gal4/UAS-dFoxO-IR (E) UAS-pll-IRV2889/+; pnr-Gal4/dFoxOΔ94 (F) UAS-pll-IRV2889/+; pnr-Gal4 dFoxOΔ94/dFoxOΔ94 (G) UAS-pll-IRV2889/+; pnr-Gal4/UAS-Pll.

Mentions: pll is ubiquitously expressed throughout development [6]. To investigate whether Pll modulates dFoxO-dependent cell death in other tissues, we knocked down pll in the notum by the pnr-Gal4 driver, and observed a loss-of-bristle phenotype in the notum (Fig 8A, 8B and 8H). This phenotype, most likely caused by cell death as expression of the apoptotic gene reaper in the notum produces a similar bristle-ablation phenotype [46], is significantly suppressed by expressing a dFoxO RNAi, or deleting one or both copies of endogenous dFoxO, or expressing Pll, but not a GFP RNAi (Fig 8C–8H). Thus, Pll negatively regulates dFoxO-dependent cell death in a non-tissue-specific manner.


Pelle Modulates dFoxO-Mediated Cell Death in Drosophila.

Wu C, Chen Y, Wang F, Chen C, Zhang S, Li C, Li W, Wu S, Xue L - PLoS Genet. (2015)

dFoxO is required for loss-of-pll induced bristle phenotype on notum.(A-G) Light micrographs showing bristles on the adult notum. Compared with the pnr-Gal4 control (A), RNAi-mediated depletion of pll in notum resulted in reduced bristle number (B), which was suppressed by knocking-down dFoxO (D), deleting one or both copies of endogenous dFoxO (E and F), or expressing Pll (G), but not by expressing a GFP RNAi that served as a negative control (C). The lower panels show high magnification view of the boxed areas in upper panels. (H) Quantification of bristles number in the boxed areas from A-G. One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001, ** P<0.01). ns stands for not significant. Detailed genotypes: (A) pnr-Gal4/+ (B) UAS-pll-IRV2889/+; pnr-Gal4/+ (C) UAS-pll-IRV2889/+; pnr-Gal4/UAS-GFP-IR (D) UAS-pll-IRV2889/+; pnr-Gal4/UAS-dFoxO-IR (E) UAS-pll-IRV2889/+; pnr-Gal4/dFoxOΔ94 (F) UAS-pll-IRV2889/+; pnr-Gal4 dFoxOΔ94/dFoxOΔ94 (G) UAS-pll-IRV2889/+; pnr-Gal4/UAS-Pll.
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pgen.1005589.g008: dFoxO is required for loss-of-pll induced bristle phenotype on notum.(A-G) Light micrographs showing bristles on the adult notum. Compared with the pnr-Gal4 control (A), RNAi-mediated depletion of pll in notum resulted in reduced bristle number (B), which was suppressed by knocking-down dFoxO (D), deleting one or both copies of endogenous dFoxO (E and F), or expressing Pll (G), but not by expressing a GFP RNAi that served as a negative control (C). The lower panels show high magnification view of the boxed areas in upper panels. (H) Quantification of bristles number in the boxed areas from A-G. One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001, ** P<0.01). ns stands for not significant. Detailed genotypes: (A) pnr-Gal4/+ (B) UAS-pll-IRV2889/+; pnr-Gal4/+ (C) UAS-pll-IRV2889/+; pnr-Gal4/UAS-GFP-IR (D) UAS-pll-IRV2889/+; pnr-Gal4/UAS-dFoxO-IR (E) UAS-pll-IRV2889/+; pnr-Gal4/dFoxOΔ94 (F) UAS-pll-IRV2889/+; pnr-Gal4 dFoxOΔ94/dFoxOΔ94 (G) UAS-pll-IRV2889/+; pnr-Gal4/UAS-Pll.
Mentions: pll is ubiquitously expressed throughout development [6]. To investigate whether Pll modulates dFoxO-dependent cell death in other tissues, we knocked down pll in the notum by the pnr-Gal4 driver, and observed a loss-of-bristle phenotype in the notum (Fig 8A, 8B and 8H). This phenotype, most likely caused by cell death as expression of the apoptotic gene reaper in the notum produces a similar bristle-ablation phenotype [46], is significantly suppressed by expressing a dFoxO RNAi, or deleting one or both copies of endogenous dFoxO, or expressing Pll, but not a GFP RNAi (Fig 8C–8H). Thus, Pll negatively regulates dFoxO-dependent cell death in a non-tissue-specific manner.

Bottom Line: Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals.Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly.This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.

ABSTRACT
Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals. Recent studies also suggest a critical role of IRAKs in tumor development, though the underlying mechanism remains elusive. Pelle is the sole Drosophila IRAK homolog implicated in the conserved Toll pathway that regulates Dorsal/Ventral patterning, innate immune response, muscle development and axon guidance. Here we report a novel function of pll in modulating apoptotic cell death, which is independent of the Toll pathway. We found that loss of pll results in reduced size in wing tissue, which is caused by a reduction in cell number but not cell size. Depletion of pll up-regulates the transcription of pro-apoptotic genes, and triggers caspase activation and cell death. The transcription factor dFoxO is required for loss-of-pll induced cell death. Furthermore, loss of pll activates dFoxO, promotes its translocation from cytoplasm to nucleus, and up-regulates the transcription of its target gene Thor/4E-BP. Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly. This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis.

No MeSH data available.


Related in: MedlinePlus