Regulation of Toll signaling and inflammation by β-arrestin and the SUMO protease Ulp1.
The Toll signaling pathway has a highly conserved function in innate immunity and is regulated by multiple factors that fine tune its activity. One such factor is β-arrestin Kurtz (Krz), which we previously implicated in the inhibition of developmental Toll signaling in the Drosophila melanogaster embryo. Another level of controlling Toll activity and immune system homeostasis is by protein sumoylation. In this study, we have uncovered a link between these two modes of regulation and show that Krz affects sumoylation via a conserved protein interaction with a SUMO protease, Ulp1. Loss of function of krz or Ulp1 in Drosophila larvae results in a similar inflammatory phenotype, which is manifested as increased lamellocyte production; melanotic mass formation; nuclear accumulation of Toll pathway transcriptional effectors, Dorsal and Dif; and expression of immunity genes, such as Drosomycin. Moreover, mutations in krz and Ulp1 show dosage-sensitive synergistic genetic interactions, suggesting that these two proteins are involved in the same pathway. Using Dorsal sumoylation as a readout, we found that altering Krz levels can affect the efficiency of SUMO deconjugation mediated by Ulp1. Our results demonstrate that β-arrestin controls Toll signaling and systemic inflammation at the level of sumoylation.
Department of Biology, University of Massachusetts Boston, Boston, Massachusetts 02125.
Saima G
SG
Anjum
Wenjian
W
Xu
Niusha
N
Nikkholgh
Sukanya
S
Basu
Yingchao
Y
Nie
Mary
M
Thomas
Mridula
M
Satyamurti
Bogdan A
BA
Budnik
Y Tony
YT
Ip
Alexey
A
Veraksa
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D058207:Sumoylation; D051193:Toll-Like Receptors / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D019390:Arrestins; D004268:DNA-Binding Proteins; C084428:Dif protein, Drosophila; D029721:Drosophila Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D051193:Toll-Like Receptors; D014157:Transcription Factors; C062236:dl protein, Drosophila; C412169:krz protein, Drosophila; D003546:Cysteine Endopeptidases; C118083:Ulp1 protease
Toll; Ulp1; arrestin; inflammation; sumoylation