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The Small Ubiquitin-related modifier (SUMO) regulates Drosophila NF-κB signaling

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dc.contributor.advisor RATNAPARKHI, GIRISH S. en_US
dc.contributor.author HEGDE, SUSHMITHA en_US
dc.date.accessioned 2022-10-25T10:16:01Z
dc.date.available 2022-10-25T10:16:01Z
dc.date.issued 2022-07 en_US
dc.identifier.citation 193 en_US
dc.identifier.uri http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/7417
dc.description.abstract In Drosophila, NF-κB signaling plays key roles in both animal development and in host defence. The activation and kinetics of the two main arms of NF-κB, the Toll and IMD pathways are regulated by post-translational modifications like phosphorylation, ubiquitination, and SUMOylation. Conjugation by SUMO (small ubiquitin-related modifier) can alter protein localization, activity, or function in a context-specific manner. Here, we have explored physiological roles for the SUMO conjugation of two proteins, Dorsal and Caspar, that are important regulators of the two major immune signalling cascades, the Toll/NF-κB and IMD/NF-κB signaling cascades respectively. For Dorsal (DL), we have generated a CRISPR-Cas9 edited variant Drosophila line that is SUMO conjugation resistant (SCR). Intriguingly, embryos laid by dlSCR mothers overcome dl haploinsufficiency and complete the developmental program. This ability appears to be a result of higher transcriptional activation by DLSCR, assessed by quantitative RNA sequencing and in-situ hybridization. In contrast, SUMOylation dampens DL transcriptional activation, ultimately conferring robustness to the dorso-ventral program. Additionally, dlSCR larvae show an increase in crystal cell numbers, stronger activation of humoral defence genes, high cactus levels and cytoplasmic stabilization of DL:Cactus complexes. A mathematical model that evaluates the contribution of the small fraction of SUMOylated DL (<5%) suggests that conjugation acts to block transcriptional activation, which is driven primarily by DL that is not SUMO conjugated. Our findings define SUMO conjugation as an important regulator of the Toll signaling cascade, in both development and host defense. Our results broadly indicate that SUMO attenuates DL at the level of transcriptional activation. For Caspar (Casp), a negative regulator of the IMD/NF-κB pathway, SUMOylation does not seem to modulate the adult immune response to gram-negative bacterial infection. Intriguingly, during the course of our studies on Casp, we have uncovered novel maternal roles for this protein. Homozygous casp loss-of function (casplof) mothers lay embryos, of which ~50% die before completing gastrulation. These embryos have defects in cell division with formation of posterior primordial germs cells significantly perturbed. Since immunoprecipitation of Casp in conjugation with mass spectrometry indicates that Transient endoplasmic Reticulum 94 (TER94), a AAA-ATPase is the major interactor for Casp, in addition to other members of the proteasomal ER-associated degradation (ERAD) pathway, we are currently exploring roles for Casp in modulating degradation of specific proteins involved either in the syncytial cell divisions or in the embryonic maternal to zygotic transition. en_US
dc.description.sponsorship CSIR en_US
dc.language.iso en en_US
dc.subject Drosophila en_US
dc.subject SUMO en_US
dc.subject NF-kB signaling en_US
dc.subject immunity en_US
dc.subject early development en_US
dc.title The Small Ubiquitin-related modifier (SUMO) regulates Drosophila NF-κB signaling en_US
dc.type Thesis en_US
dc.description.embargo One Year en_US
dc.type.degree Int.Ph.D en_US
dc.contributor.department Dept. of Biology en_US
dc.contributor.registration 20152016 en_US


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  • PhD THESES [599]
    Thesis submitted to IISER Pune in partial fulfilment of the requirements for the degree of Doctor of Philosophy

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