Background: Caspases are cysteine proteases with essential functions in the apoptotic pathway; their proteolytic activity toward various substrates is associated with the morphological changes of cells. Recent reports have described non-apoptotic functions of caspases, including autophagy. In this report, we searched for novel modifiers of the phenotype of Dcp-1 gain-of-function (GF) animals by screening promoter element- inserted Drosophila melanogaster lines (EP lines).Results: We screened ~15,000 EP lines and identified 72 Dcp-1-interacting genes that were classified into 10 groups based on their functions and pathways: 4 apoptosis signaling genes, 10 autophagy genes, 5 insulin/IGF and TOR signaling pathway genes, 6 MAP kinase and JNK signaling pathway genes, 4 ecdysone signaling genes, 6 ubiquitination genes, 11 various developmental signaling genes, 12 transcription factors, 3 translation factors, and 11 other unclassified genes including 5 functionally undefined genes. Among them, insulin/IGF and TOR signaling pathway, MAP kinase and JNK signaling pathway, and ecdysone signaling are known to be involved in autophagy. Together with the identification of autophagy genes, the results of our screen suggest that autophagy counteracts Dcp-1-induced apoptosis. Consistent with this idea, we show that expression of eGFP-Atg5 rescued the eye phenotype caused by Dcp-1 GF. Paradoxically, we found that over-expression of full-length Dcp-1 induced autophagy, as Atg8b-GFP, an indicator of autophagy, was increased in the eye imaginal discs and in the S2 cell line. Taken together, these data suggest that autophagy suppresses Dcp-1-mediated apoptotic cell death, whereas Dcp-1 positively regulates autophagy, possibly through feedback regulation.Conclusions: We identified a number of Dcp-1 modifiers that genetically interact with Dcp-1-induced cell death. Our results showing that Dcp-1 and autophagy-related genes influence each other will aid future investigations of the complicated relationships between apoptosis and autophagy.
Bibliographical noteFunding Information:
We thank Dr. Jongkyeong Chung for providing signaling gene-related strains; Dr. Thomas P. Neufeld for the hsp70-regulated GFP-Atg8, UAS-S6kFb2 and the UAS-dS6k fly lines; Dr. Ryan Scott in the Neufeld laboratory for the pHS-GA8 construct; Dr. Herald Stenmark for the UAS-Atg5 GFP line; and Dr. Kimberly McCall for caspase lines. This research was supported by a grant from the Molecular Biomedical Research Program (M1-0106-05-0000), the Molecular and Cellular Bio Discovery Research Program (M1-0106-00-0200) of the Ministry Of Science and Technology of Korea and New Drug Target Discovery through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0083353) to OJY, and Korean government grant World Class University Program (R31-2008-000-10100-0) to SJL.
ASJC Scopus subject areas
- Cell Biology