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.
Highlights
Interleukin-1 receptor-associated kinases (IRAKs) are evolutionarily conserved Serine/Threonine (Ser/Thr) kinases that modulates Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs) signaling in the immune and inflammation response [1,2,3]
In the present study we report a Toll pathway independent function of Pll in modulating apoptotic cell death
Our major findings include: 1) loss of pll generates Toll pathwayindependent wing phenotypes, which are caused by a reduction in cell number but not cell size; 2) depletion of pll up-regulates the transcription of pro-apoptotic genes hid, reaper and grim, and triggers caspase-mediated cell death, whereas cell proliferation remains unaffected; 3) pll modulates caspase activation and cell death through the transcription factor dFoxO; 4) loss of pll promotes dFoxO translocation from cytoplasm to nucleus, and activates the transcription of dFoxO target gene Thor/4E-BP; 5) Pll physically interacts
Summary
Interleukin-1 receptor-associated kinases (IRAKs) are evolutionarily conserved Serine/Threonine (Ser/Thr) kinases that modulates Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs) signaling in the immune and inflammation response [1,2,3]. The Toll pathway in Drosophila has been implicated as a crucial regulator in embryonic Dorsal/Ventral (D/V) patterning [8,9], innate immune response against Gram-positive bacteria and fungi [10], proper muscle development and axon guidance [11,12]. This pathway is equivalent to the mammalian IL-1R/TLR pathway, with Toll/Cactus/Dorsal representing the respective homologs of IL-1R/IκB/NF-κB [13]. Besides its role in the conserved pathway, it remains unknown whether Pll performs any Toll pathway independent functions in vivo
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