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Windpipe controls Drosophila intestinal homeostasis by regulating JAK/STAT pathway via promoting receptor endocytosis and lysosomal degradation.

Ren W, Zhang Y, Li M, Wu L, Wang G, Baeg GH, You J, Li Z, Lin X - PLoS Genet. (2015)

Bottom Line: Loss of wdp activity results in the disruption of midgut homeostasis under normal and regenerative conditions.Importantly, we show that Wdp interacts with the receptor Domeless (Dome), and promotes its internalization for subsequent lysosomal degradation.Together, these data led us to propose that Wdp acts as a novel negative feedback regulator of the JAK/STAT pathway in regulating intestinal homeostasis.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.

ABSTRACT
The adult intestinal homeostasis is tightly controlled by proper proliferation and differentiation of intestinal stem cells. The JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway is essential for the regulation of adult stem cell activities and maintenance of intestinal homeostasis. Currently, it remains largely unknown how JAK/STAT signaling activities are regulated in these processes. Here we have identified windpipe (wdp) as a novel component of the JAK/STAT pathway. We demonstrate that Wdp is positively regulated by JAK/STAT signaling in Drosophila adult intestines. Loss of wdp activity results in the disruption of midgut homeostasis under normal and regenerative conditions. Conversely, ectopic expression of Wdp inhibits JAK/STAT signaling activity. Importantly, we show that Wdp interacts with the receptor Domeless (Dome), and promotes its internalization for subsequent lysosomal degradation. Together, these data led us to propose that Wdp acts as a novel negative feedback regulator of the JAK/STAT pathway in regulating intestinal homeostasis.

No MeSH data available.


Related in: MedlinePlus

Model for the function of Wdp.During tissue damage or pathogen infection induced midgut regeneration, the JAK/STAT pathway is highly activated (A). In response to extracellular signaling, STAT92E dimers translocate into the nucleus, bind to its consensus binding sites at the genomic region of wdp and then promote its transcription. Newly synthesized Wdp protein is transported to the cell membrane, where it interacts with Dome and promotes Dome internalization from the cell membrane finally into the lysosomes for subsequent degradation (B). Through this negative feedback manner, Wdp restricts the signal duration and ensures JAK/STAT signaling returns to the normal levels after injury in Drosophila intestines.
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pgen.1005180.g008: Model for the function of Wdp.During tissue damage or pathogen infection induced midgut regeneration, the JAK/STAT pathway is highly activated (A). In response to extracellular signaling, STAT92E dimers translocate into the nucleus, bind to its consensus binding sites at the genomic region of wdp and then promote its transcription. Newly synthesized Wdp protein is transported to the cell membrane, where it interacts with Dome and promotes Dome internalization from the cell membrane finally into the lysosomes for subsequent degradation (B). Through this negative feedback manner, Wdp restricts the signal duration and ensures JAK/STAT signaling returns to the normal levels after injury in Drosophila intestines.

Mentions: On the basis of our findings, the following model is proposed (Fig 8A and 8B): Wdp regulates intestinal homeostasis through its modulation of JAK/STAT signaling. Under physical conditions, low levels of Wdp in progenitors are needed to maintain proper levels of JAK/STAT signaling activity, while high levels of Wdp in ECs reduce Dome levels to ensure these cells are insensitive to JAK/STAT signaling. When midgut epithelium is damaged by environmental challenges, high levels of JAK/STAT signaling activity are induced to replenish the damaged midgut. Then Wdp expression is highly induced in the intestines to reduce Dome levels, thereby switching off the overactivated JAK/STAT signaling. Through this way, ISC proliferative rate returns to normal levels to avoid tissue hyperplasia. While other mechanisms or regulators are likely to be involved in regulating intestinal homeostasis, our data suggest that Wdp is one of the key regulators in this process through interfering with JAK/STAT signaling activity.


Windpipe controls Drosophila intestinal homeostasis by regulating JAK/STAT pathway via promoting receptor endocytosis and lysosomal degradation.

Ren W, Zhang Y, Li M, Wu L, Wang G, Baeg GH, You J, Li Z, Lin X - PLoS Genet. (2015)

Model for the function of Wdp.During tissue damage or pathogen infection induced midgut regeneration, the JAK/STAT pathway is highly activated (A). In response to extracellular signaling, STAT92E dimers translocate into the nucleus, bind to its consensus binding sites at the genomic region of wdp and then promote its transcription. Newly synthesized Wdp protein is transported to the cell membrane, where it interacts with Dome and promotes Dome internalization from the cell membrane finally into the lysosomes for subsequent degradation (B). Through this negative feedback manner, Wdp restricts the signal duration and ensures JAK/STAT signaling returns to the normal levels after injury in Drosophila intestines.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414558&req=5

pgen.1005180.g008: Model for the function of Wdp.During tissue damage or pathogen infection induced midgut regeneration, the JAK/STAT pathway is highly activated (A). In response to extracellular signaling, STAT92E dimers translocate into the nucleus, bind to its consensus binding sites at the genomic region of wdp and then promote its transcription. Newly synthesized Wdp protein is transported to the cell membrane, where it interacts with Dome and promotes Dome internalization from the cell membrane finally into the lysosomes for subsequent degradation (B). Through this negative feedback manner, Wdp restricts the signal duration and ensures JAK/STAT signaling returns to the normal levels after injury in Drosophila intestines.
Mentions: On the basis of our findings, the following model is proposed (Fig 8A and 8B): Wdp regulates intestinal homeostasis through its modulation of JAK/STAT signaling. Under physical conditions, low levels of Wdp in progenitors are needed to maintain proper levels of JAK/STAT signaling activity, while high levels of Wdp in ECs reduce Dome levels to ensure these cells are insensitive to JAK/STAT signaling. When midgut epithelium is damaged by environmental challenges, high levels of JAK/STAT signaling activity are induced to replenish the damaged midgut. Then Wdp expression is highly induced in the intestines to reduce Dome levels, thereby switching off the overactivated JAK/STAT signaling. Through this way, ISC proliferative rate returns to normal levels to avoid tissue hyperplasia. While other mechanisms or regulators are likely to be involved in regulating intestinal homeostasis, our data suggest that Wdp is one of the key regulators in this process through interfering with JAK/STAT signaling activity.

Bottom Line: Loss of wdp activity results in the disruption of midgut homeostasis under normal and regenerative conditions.Importantly, we show that Wdp interacts with the receptor Domeless (Dome), and promotes its internalization for subsequent lysosomal degradation.Together, these data led us to propose that Wdp acts as a novel negative feedback regulator of the JAK/STAT pathway in regulating intestinal homeostasis.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.

ABSTRACT
The adult intestinal homeostasis is tightly controlled by proper proliferation and differentiation of intestinal stem cells. The JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway is essential for the regulation of adult stem cell activities and maintenance of intestinal homeostasis. Currently, it remains largely unknown how JAK/STAT signaling activities are regulated in these processes. Here we have identified windpipe (wdp) as a novel component of the JAK/STAT pathway. We demonstrate that Wdp is positively regulated by JAK/STAT signaling in Drosophila adult intestines. Loss of wdp activity results in the disruption of midgut homeostasis under normal and regenerative conditions. Conversely, ectopic expression of Wdp inhibits JAK/STAT signaling activity. Importantly, we show that Wdp interacts with the receptor Domeless (Dome), and promotes its internalization for subsequent lysosomal degradation. Together, these data led us to propose that Wdp acts as a novel negative feedback regulator of the JAK/STAT pathway in regulating intestinal homeostasis.

No MeSH data available.


Related in: MedlinePlus