Regulation of Toll Signaling and Inflammation by β-Arrestin and the SUMO Protease Ulp1

Anjum, Saima; Xu, Wenjian; Nikkholgh, Niusha; Basu, Sukanya; Nie, Yulun; Thomas, Mary C.; Satyamurti, Mridula; Budnik, Bogdan; Ip, Y. Tony; Veraksa, Alexey

doi:10.1534/genetics.113.157859

Cited by 36 publications

(77 citation statements)

References 53 publications

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“…Inappropriate activation of inflammatory responses or lack of immune signaling lead to serious conditions such as inflammatory diseases or immunodeficiency, respectively. Recent studies reveal that innate immunity is regulated by multiple factors, including sumoylation and the retromer complex, which fine tune immune activity (32,33). The present study clearly showed that glycosylation plays an important role in maintaining innate immune homeostasis and activation of immune responses.…”

Section: Discussionsupporting

confidence: 63%

Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation

Yamamoto-Hino

Muraoka

Kondo

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The innate immune system is the first line of defense encountered by invading pathogens. Delayed and/or inadequate innate immune responses can result in failure to combat pathogens, whereas excessive and/or inappropriate responses cause runaway inflammation. Therefore, immune responses are tightly regulated from initiation to resolution and are repressed during the steady state. It is well known that glycans presented on pathogens play important roles in pathogen recognition and the interactions between host molecules and microbes; however, the function of glycans of host organisms in innate immune responses is less well known. Here, we show that innate immune quiescence and strength of the immune response are controlled by host glycosylation involving a novel UDPgalactose transporter called Senju. In senju mutants, reduced expression of galactose-containing glycans resulted in hyperactivation of the Toll signaling pathway in the absence of immune challenges. Genetic epistasis and biochemical analyses revealed that Senju regulates the Toll signaling pathway at a step that converts Toll ligand Spatzle to its active form. Interestingly, Toll activation in immune-challenged wild type (WT) flies reduced the expression of galactose-containing glycans. Suppression of the degalactosylation by senju overexpression resulted in reduced induction of Toll-dependent expression of an antimicrobial peptide, Drosomycin, and increased susceptibility to infection with Gram-positive bacteria. These data suggest that Senju-mediated galactosylation suppresses undesirable Toll signaling activation during the steady state; however, Toll activation in response to infection leads to degalactosylation, which raises the immune response to an adequate level and contributes to the prompt elimination of pathogens.innate immunity | glycosylation | Toll pathway | nucleotide sugar transporter | galactose

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Section: Discussionsupporting

confidence: 63%

Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation

Yamamoto-Hino

Muraoka

Kondo

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The activation of the Toll pathway is also negatively regulated by serpins (13). Kurtz, a ␤-arrestin in Drosophila, negatively controls Toll signaling and systemic inflammation at the level of sumoylation (14). A very recent report demonstrates that Drosophila Pellino functions as a negative regulator by targeting MyD88 for ubiquitination and degradation in Toll-mediated signaling (15).…”

Section: (3)mentioning

confidence: 99%

“…In Drosophila, Kurtz inhibits MAPK and Toll signaling during development (24). Another study connected Kurtz activity to sumoylation and found that Kurtz negatively controls Toll signaling and systemic inflammation at the level of sumoylation in Drosophila, although the mechanism was not clear (14). Therefore, mammalian ␤arrs and Drosophila Kurtz both downregulate NF-B signaling, but in different ways.…”

Section: (3)mentioning

confidence: 99%

β-Arrestins Negatively Regulate the Toll Pathway in Shrimp by Preventing Dorsal Translocation and Inhibiting Dorsal Transcriptional Activity

Sun

Lan

Shi

et al. 2016

Journal of Biological Chemistry

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The Toll signaling pathway plays an important role in the innate immunity of Drosophila melanogaster and mammals. The activation and termination of Toll signaling are finely regulated in these animals. Although the primary components of the Toll pathway were identified in shrimp, the functions and regulation of the pathway are seldom studied. We first demonstrated that the Toll signaling pathway plays a central role in host defense against Staphylococcus aureus by regulating expression of antimicrobial peptides in shrimp. We then found that ␤-arrestins negatively regulate Toll signaling in two different ways. ␤-Arrestins interact with the C-terminal PEST domain of Cactus through the arrestin-N domain, and Cactus interacts with the RHD domain of Dorsal via the ankyrin repeats domain, forming a heterotrimeric complex of ␤-arrestin⅐Cactus⅐ Dorsal, with Cactus as the bridge. This complex prevents Cactus phosphorylation and degradation, as well as Dorsal translocation into the nucleus, thus inhibiting activation of the Toll signaling pathway. ␤-Arrestins also interact with non-phosphorylated ERK (extracellular signal-regulated protein kinase) through the arrestin-C domain to inhibit ERK phosphorylation, which affects Dorsal translocation into the nucleus and phosphorylation of Dorsal at Ser 276 that impairs Dorsal transcriptional activity. Our study suggests that ␤-arrestins negatively regulate the Toll signaling pathway by preventing Dorsal translocation and inhibiting Dorsal phosphorylation and transcriptional activity.

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“…Furthermore a mutation in Krz and Ulp1 causes similar dose dependent synergistic effects providing grounds for the two proteins involvement in same pathway. The altered levels of Krz can affect the deconjugation ability of Ulp1 so is involved in controlling systemic inflammation and toll signalling at SUMOylation level (Anjum et al, 2013). As the interaction between β-arrestin and SENP1 is conserved it can be suspected that the control mechanism might be similar in other organisms.…”

Section: Sumoylation and Inflammatory Pathwaymentioning

confidence: 99%

“…As the interaction between β-arrestin and SENP1 is conserved it can be suspected that the control mechanism might be similar in other organisms. This will be of interest to see whether mammalian β -arrestins have role in Toll/NFkB signalling regulation (Anjum et al, 2013 RelA, is involved in NFkB heterodimer formation, nuclear translocation and activation. A recent report of the negative regulation of PIAS3 mediated SUMOylation of RelA subuunit of NFkB is surfaced unearthing the biochemical mechanism of transcriptional suppression (Liu et al, 2012).…”

mentioning

confidence: 99%

SUMOylation: A link to future therapeutics

2016

Current Issues in Molecular Biology

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SUMOylation, much of a similar process like ubiquitination catches attention across various research groups as a potential therapeutic target to fight various infectious and cancerous diseases. This idea take its strength from recent reports which unearth the molecular mechanisms of SUMOylation and its involvement in important diseases distributed across various kingdoms. At the beginning SUMOylation was considered a process affected only by viral diseases but subsequent reports enlighten its role in diseases caused by bacteria as well. This enhances the SUMOylation canvas and demanded more in-depth study of the process. The present review is an attempt to study the regulatory mechanism of genes when the natural SUMOylation pathway is disturbed, the cross-talk among SUMOylation and other post translational modifications, the role of miRNAs in controlling the function of transcripts, loading of RNA species into exosomes and the possible SUMOylation related therapeutic targets. IntroductionThe innate immune responses across kingdoms are tightly regulated to fight attacking pathogens. Post translational modification of proteins like acetylation, methylation, ubiquitination and SUMOylation have predominant role in activation/deactivation of immune responses by regulating various cellular processes including transcription, DNA repair, proliferation and apoptosis as these have the potential to relocate the protein to different organelles and modify its biological function. The deep understanding of those post translational mechanisms could provide insights in controlling several disease conditions and develop therapeutics based on those post translational modification markers.The small ubiquitin like modifiers (SUMO) proteins discovered in 1997 (Mahajan et al., 1997) has since been recognized as family of important modification proteins unlike ubiquitination which is involved in degradation of proteins, instead it modulates the function of target proteins. The covalent conjugation of SUMO molecules to protein residue lysine on a typical consensus sequence ψKxD/E (where ψ is large hydrophobic residue, K is the target lysine, D/E is acidic residue and x represent any amino acid) (Rodriguez et al., 2001;Sampson et al., 2001). The process of SUMOylation is carried out by a cascade of three enzymes (E1, E2 and E3). E1 is a SUMO activating enzyme SAE1, while E2 is conjugating enzyme e.g. Ubc9 and E3 is SUMO ligase. The SUMOylation reaction is reversed by SENPs termed as deSUMOylation having distinct regulatory roles. Till date four SUMO molecules have been reported in mammals viz., SUMO1, SUMO2, SUMO3 and SUMO4. The sequence similarity of SUMO2 and SUMO3 are almost 97% hence are often reported collectively as SUMO2/3. Various kinds of stimuli like oxidative stress often increase the rate of SUMOylation. A recent report shows the exposure to cigarette smoke alters the microRNA expression by SUMOylation of DICER (Gross et al., 2014). Viruses and chemical toxins also causes an increase in SUMOylation, a well known exam...

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Regulation of Toll Signaling and Inflammation by β-Arrestin and the SUMO Protease Ulp1

Cited by 36 publications

References 53 publications

Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation

Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation

β-Arrestins Negatively Regulate the Toll Pathway in Shrimp by Preventing Dorsal Translocation and Inhibiting Dorsal Transcriptional Activity

SUMOylation: A link to future therapeutics

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