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Review
. 2018 Jan 1;6(1):2.
doi: 10.3390/jdb6010002.

The Biology of SUMO-Targeted Ubiquitin Ligases in Drosophila Development, Immunity, and Cancer

Mona Abed  1 , Eliya Bitman-Lotan  2 , Amir Orian  3
Affiliations
Review

The Biology of SUMO-Targeted Ubiquitin Ligases in Drosophila Development, Immunity, and Cancer

Mona Abed et al. J Dev Biol. .

Abstract

The ubiquitin and SUMO (small ubiquitin-like modifier) pathways modify proteins that in turn regulate diverse cellular processes, embryonic development, and adult tissue physiology. These pathways were originally discovered biochemically in vitro, leading to a long-standing challenge of elucidating both the molecular cross-talk between these pathways and their biological importance. Recent discoveries in Drosophila established that ubiquitin and SUMO pathways are interconnected via evolutionally conserved SUMO-targeted ubiquitin ligase (STUbL) proteins. STUbL are RING ubiquitin ligases that recognize SUMOylated substrates and catalyze their ubiquitination, and include Degringolade (Dgrn) in Drosophila and RNF4 and RNF111 in humans. STUbL are essential for early development of both the fly and mouse embryos. In the fly embryo, Dgrn regulates early cell cycle progression, sex determination, zygotic gene transcription, segmentation, and neurogenesis, among other processes. In the fly adult, Dgrn is required for systemic immune response to pathogens and intestinal stem cell regeneration upon infection. These functions of Dgrn are highly conserved in humans, where RNF4-dependent ubiquitination potentiates key oncoproteins, thereby accelerating tumorigenesis. Here, we review the lessons learned to date in Drosophila and highlight their relevance to cancer biology.

Keywords: Dgrn; SUMO; SUMO-targeted ubiquitin ligases RNF4; cancer; development; gene regulation; immunity; transcription; ubiquitin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of STUbL protein and a putative role for Dgrn in the regulation of co-factors selection. (A) Schematic diagram of human and Drosophila STUbL proteins (not to scale). SIM, SUMO-interacting motif; NTR, nucleosome-targeting region; ARM, arginine-rich region, and PRR are highly conserved amino acids within the ARM; RING, Really Interesting New Gene catalytic domain. “?” denotes putative domains. (B) A model for the Dgrn-dependent inactivation of Hairy-Gro interaction, see text for details.
Figure 2
Figure 2
Post-transcriptional regulation of Ftz during segmentation. Cartoon depicting the pattern of Ftz protein during segmentation. (A) Endogenous Ftz protein expression is limited to seven stripes. (B) Ftz protein expression is extended in hairy mutants. (C) Ftz expression in hairy mutant embryos that are also heterozygous for dgrnDK (hairy; dgrnDK/+) is greatly restored [17]. (D) Ftz protein expression is reduced in Dgrn-null embryos [16]. (E) Ftz protein expression is expanded in ftzUal embryos harboring mutations in a short “stability” motif that is required for Ftz degradation [44].
Figure 3
Figure 3
Processes and key proteins regulated by Dgrn and RNF4 in Drosophila and humans. In the developing embryo, Dgrn is required to resolve DSBs, and a similar function was attributed to RNF4 upon DNA damage in mouse and humans. In transcription, Dgrn determines co-factor choice during transcriptional repression limiting Hairy, Deadpan (Dpn), and HES E(spl) activity during segmentation, sex determination, and neurogenesis. Dgrn and RNF4 also enhance transcriptional activation. Dgrn is required for the expression of early zygotic genes such as twist, and zen downstream targets of the Toll and Dpp pathways. In the adult fly, Dgrn is required for the transcription of AMP genes, and for Notch-dependent transcription and gut regeneration. Likewise, RNF4 stabilizes and potentiates the transcriptional activity of c-Myc, c-Jun, and β-catenin promoting tumorigenesis of cancer cells. In contrast, in the context of promyelocytic leukemia, RNF4 ubiquitinates and targets the SUMOylated oncogenic PML-RAR for degradation, which suppresses tumorigenesis.
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