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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

pll regulates cell number, but not cell size in adult wing.(A-D, F-I and K-N) Light micrographs of Drosophila adult wings are shown, anterior is to the left and distal up. Compared with the Gal4 controls (A, F and K), expression of pll RNAi (pll-IRV2889) driven by Omb-Gal4 (B), Sd-Gal4 (G) or en-Gal4 (L) resulted in reduced wing tissue in the corresponding areas, which were rescued by expression of Pll (D, I and N), but not that of GFP (C, H and M). (E and J) Quantifications of adult wing size/wild type (WT) ratio are shown for figures A-D and F-I respectively (n = 10). One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001). (O and P) Quantifications of cell size (O) and cell number (P) in wings shown in K and L. The P/A ratio of cell size showed no difference while that of cell number decreased significantly when pll was knocked down in the P compartment by en-Gal4. Unpaired t test was used to calculate statistical significance, indicated with asterisks (*** P<0.001, n = 10 in each group). (Q) Statistic analysis of total size P/A ratio are shown for figures K-N. One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001). ns stands for not significant. Detailed genotypes: (A) Omb-Gal4/+ (B) Omb-Gal4/+; UAS-pll-IRV2889/+ (C) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (D) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (F) Sd-Gal4/+ (G) Sd-Gal4/+; UAS-pll-IRV2889/+ (H) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (I) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (K) en-Gal4/+ (L) en-Gal4/UAS-pll-IRV2889 (M) en-Gal4/UAS-pll-IRV2889; UAS-GFP/+ (N) en-Gal4/UAS-pll-IRV2889; UAS-Pll/+.
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pgen.1005589.g002: pll regulates cell number, but not cell size in adult wing.(A-D, F-I and K-N) Light micrographs of Drosophila adult wings are shown, anterior is to the left and distal up. Compared with the Gal4 controls (A, F and K), expression of pll RNAi (pll-IRV2889) driven by Omb-Gal4 (B), Sd-Gal4 (G) or en-Gal4 (L) resulted in reduced wing tissue in the corresponding areas, which were rescued by expression of Pll (D, I and N), but not that of GFP (C, H and M). (E and J) Quantifications of adult wing size/wild type (WT) ratio are shown for figures A-D and F-I respectively (n = 10). One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001). (O and P) Quantifications of cell size (O) and cell number (P) in wings shown in K and L. The P/A ratio of cell size showed no difference while that of cell number decreased significantly when pll was knocked down in the P compartment by en-Gal4. Unpaired t test was used to calculate statistical significance, indicated with asterisks (*** P<0.001, n = 10 in each group). (Q) Statistic analysis of total size P/A ratio are shown for figures K-N. One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001). ns stands for not significant. Detailed genotypes: (A) Omb-Gal4/+ (B) Omb-Gal4/+; UAS-pll-IRV2889/+ (C) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (D) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (F) Sd-Gal4/+ (G) Sd-Gal4/+; UAS-pll-IRV2889/+ (H) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (I) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (K) en-Gal4/+ (L) en-Gal4/UAS-pll-IRV2889 (M) en-Gal4/UAS-pll-IRV2889; UAS-GFP/+ (N) en-Gal4/UAS-pll-IRV2889; UAS-Pll/+.

Mentions: To further characterize the physiological function of pll in wing development, we knocked down pll in distinct regions of the wing disc by using additional wing specific Gal4 drivers: Optomotor-blind (Omb)-Gal4, Scalloped (Sd)-Gal4 and engrailed (en)-Gal4. We noted that loss of pll in the distal part (Omb>pll-IR), wing pouch (Sd>pll-IR) or posterior compartment (en>pll-IR) of the wing disc caused severe reduction in corresponding areas of the adult wing, which were rescued by co-expression of Pll, but not that of GFP (Fig 2A–2N and 2Q; S3 Fig), confirming that pll is required for proper wing development.


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)

pll regulates cell number, but not cell size in adult wing.(A-D, F-I and K-N) Light micrographs of Drosophila adult wings are shown, anterior is to the left and distal up. Compared with the Gal4 controls (A, F and K), expression of pll RNAi (pll-IRV2889) driven by Omb-Gal4 (B), Sd-Gal4 (G) or en-Gal4 (L) resulted in reduced wing tissue in the corresponding areas, which were rescued by expression of Pll (D, I and N), but not that of GFP (C, H and M). (E and J) Quantifications of adult wing size/wild type (WT) ratio are shown for figures A-D and F-I respectively (n = 10). One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001). (O and P) Quantifications of cell size (O) and cell number (P) in wings shown in K and L. The P/A ratio of cell size showed no difference while that of cell number decreased significantly when pll was knocked down in the P compartment by en-Gal4. Unpaired t test was used to calculate statistical significance, indicated with asterisks (*** P<0.001, n = 10 in each group). (Q) Statistic analysis of total size P/A ratio are shown for figures K-N. One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001). ns stands for not significant. Detailed genotypes: (A) Omb-Gal4/+ (B) Omb-Gal4/+; UAS-pll-IRV2889/+ (C) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (D) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (F) Sd-Gal4/+ (G) Sd-Gal4/+; UAS-pll-IRV2889/+ (H) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (I) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (K) en-Gal4/+ (L) en-Gal4/UAS-pll-IRV2889 (M) en-Gal4/UAS-pll-IRV2889; UAS-GFP/+ (N) en-Gal4/UAS-pll-IRV2889; UAS-Pll/+.
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pgen.1005589.g002: pll regulates cell number, but not cell size in adult wing.(A-D, F-I and K-N) Light micrographs of Drosophila adult wings are shown, anterior is to the left and distal up. Compared with the Gal4 controls (A, F and K), expression of pll RNAi (pll-IRV2889) driven by Omb-Gal4 (B), Sd-Gal4 (G) or en-Gal4 (L) resulted in reduced wing tissue in the corresponding areas, which were rescued by expression of Pll (D, I and N), but not that of GFP (C, H and M). (E and J) Quantifications of adult wing size/wild type (WT) ratio are shown for figures A-D and F-I respectively (n = 10). One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001). (O and P) Quantifications of cell size (O) and cell number (P) in wings shown in K and L. The P/A ratio of cell size showed no difference while that of cell number decreased significantly when pll was knocked down in the P compartment by en-Gal4. Unpaired t test was used to calculate statistical significance, indicated with asterisks (*** P<0.001, n = 10 in each group). (Q) Statistic analysis of total size P/A ratio are shown for figures K-N. One-way ANOVA with Bonferroni multiple comparison test was used to compute P-values, significance is indicated with asterisks (*** P<0.001). ns stands for not significant. Detailed genotypes: (A) Omb-Gal4/+ (B) Omb-Gal4/+; UAS-pll-IRV2889/+ (C) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (D) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (F) Sd-Gal4/+ (G) Sd-Gal4/+; UAS-pll-IRV2889/+ (H) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (I) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (K) en-Gal4/+ (L) en-Gal4/UAS-pll-IRV2889 (M) en-Gal4/UAS-pll-IRV2889; UAS-GFP/+ (N) en-Gal4/UAS-pll-IRV2889; UAS-Pll/+.
Mentions: To further characterize the physiological function of pll in wing development, we knocked down pll in distinct regions of the wing disc by using additional wing specific Gal4 drivers: Optomotor-blind (Omb)-Gal4, Scalloped (Sd)-Gal4 and engrailed (en)-Gal4. We noted that loss of pll in the distal part (Omb>pll-IR), wing pouch (Sd>pll-IR) or posterior compartment (en>pll-IR) of the wing disc caused severe reduction in corresponding areas of the adult wing, which were rescued by co-expression of Pll, but not that of GFP (Fig 2A–2N and 2Q; S3 Fig), confirming that pll is required for proper wing development.

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