The Drosophila ubiquitin-specific protease dUSP36/Scny targets IMD to prevent constitutive immune signaling.
Ubiquitin proteases remove ubiquitin monomers or polymers to modify the stability or activity of proteins and thereby serve as key regulators of signal transduction. Here, we describe the function of the Drosophila ubiquitin-specific protease 36 (dUSP36) in negative regulation of the immune deficiency (IMD) pathway controlled by the IMD protein. Overexpression of catalytically active dUSP36 ubiquitin protease suppresses fly immunity against Gram-negative pathogens. Conversely, silencing dUsp36 provokes IMD-dependent constitutive activation of IMD-downstream Jun kinase and NF-kappaB signaling pathways but not of the Toll pathway. This deregulation is lost in axenic flies, indicating that dUSP36 prevents constitutive immune signal activation by commensal bacteria. dUSP36 interacts with IMD and prevents K63-polyubiquitinated IMD accumulation while promoting IMD degradation in vivo. Blocking the proteasome in dUsp36-expressing S2 cells increases K48-polyubiquitinated IMD and prevents its degradation. Our findings identify dUSP36 as a repressor whose IMD deubiquitination activity prevents nonspecific activation of innate immune signaling.
Thevenon
Dominique
D
CEA, DSV, iRTSV, LTS, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire de Transduction du Signal, CEA Grenoble, 38054 Grenoble, France.
Engel
Elodie
E
Avet-Rochex
Amélie
A
Gottar
Marie
M
Bergeret
Evelyne
E
Tricoire
Hervé
H
Benaud
Christelle
C
Baudier
Jacques
J
Taillebourg
Emmanuel
E
Fauvarque
Marie-Odile
MO
D000818:Animals; D004330:Drosophila / Q000276:immunology*; D029721:Drosophila Proteins / Q000502:physiology*; D010450:Endopeptidases / Q000502:physiology*; D018628:Gene Dosage; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005856:Germ-Free Life / Q000276:immunology; D006090:Gram-Negative Bacteria / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D016328:NF-kappa B / Q000096:biosynthesis; D025941:Protein Interaction Mapping; D015398:Signal Transduction
D029721:Drosophila Proteins; D016328:NF-kappa B; C439909:imd protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; D010450:Endopeptidases; C534688:ubiquitin specific protease 36, Drosophila