SUMO regulates somatic cyst stem cells maintenance and directly targets hedgehog pathway in adult Drosophila testis

Abstract

SUMO (Small ubiquitin-related modifier) modification (SUMOylation) is a highly dynamic post-translational modification (PTM) that plays important roles in tissue development and disease progression. However, its function in adult stem cell maintenance is largely unknown. Here, we report the function of SUMOylation in somatic cyst stem cell (CySC) self-renewal in adult Drosophila testis. The SUMO pathway cell-autonomously regulates CySC maintenance. Reduction of SUMOylation promotes premature differentiation of CySCs and impedes the proliferation of CySCs, which leads to a reduction in the number of CySCs. Consistent with this, CySC clones carrying a mutation of the SUMO-conjugating enzyme are rapidly lost. Furthermore, inhibition of the SUMO pathway phenocopies disruption of the Hedgehog (Hh) pathway, and can block the proliferation of CySCs induced by Hh activation. Importantly, the SUMO pathway directly regulates the SUMOylation of Hh pathway transcription factor Cubitus interruptus (Ci), which is required for promoting CySC proliferation. Thus, we conclude that SUMO directly targets the Hh pathway and regulates CySC maintenance in adult Drosophila testis.

SUMOylation controls stem cell proliferation and regional cell death through Hedgehog signaling in planarians

“…The role of Ubc9 in regulating stem cells depends on the context and the experimental models in which the studies are performed [42][43][44][45]. For example, Ubc9 function is required for embryonic stem cell survival in vitro and reprogramming of induced pluripotent cells (iPS) but Ubc9 function is not pertinent to the maintenance of mouse embryonic fibroblasts (MEFs) [46].…”

DeSUMOylation of Gli1 by SENP1 Attenuates Sonic Hedgehog Signaling

“…In one report, forced expression of the putative Gli SUMOylation E3 ligase PIAS1 in chicken embryos was shown to increase Gli activity and cause ectopic expression of a Gli target gene in the neural tube (42). This positive role was corroborated in a separate study that showed that mutating 10 lysine residues of possible SUMOylation sites in Ci abolished the transcriptional activity of the mutant Ci in the Drosophila testis (44). However, another report showed that mutating Gli2 SUMOylation sites significantly increased Gli2 transcriptional activity both in a cell-based assay and in mice, possibly because these sites were also shown to be required for recruiting the histone modifier HDAC5, which represses transcription (43).…”

“…Several recent studies showing SUMOylation of Gli proteins have been reported (42)(43)(44), revealing that all 3 Gli proteins are modified at several phylogenetically conserved sites encompassing the consensus sequence ⌿KXE, but these studies diverge on the role of this modification in Shh signaling. In one report, forced expression of the putative Gli SUMOylation E3 ligase PIAS1 in chicken embryos was shown to increase Gli activity and cause ectopic expression of a Gli target gene in the neural tube (42).…”

“…Nevertheless, SUMOylation was shown to play important roles in regulating neural-tube development in vertebrates and somatic cyst stem cell self-renewal in the adult Drosophila testis (42,44). We have tested all 6 mammalian SENPs for their involvement in Shh signaling and report here that SENP1 is a specific deSUMOylation enzyme for Gli1.…”

“…Recently, all three Gli proteins in mammals, as well as their Drosophila counterpart, Ci, were shown to be SUMOylated at specific sites, but the functional impacts of these modifications differ among different reports (42)(43)(44). Nevertheless, SUMOylation was shown to play important roles in regulating neural-tube development in vertebrates and somatic cyst stem cell self-renewal in the adult Drosophila testis (42,44).…”