p47 licenses activation of the immune deficiency pathway in the tick Ixodes scapularis

Proc Natl Acad Sci U S A. 2019 Jan 2;116(1):205-210. doi: 10.1073/pnas.1808905116. Epub 2018 Dec 17.


The E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) acts as a molecular rheostat for the immune deficiency (IMD) pathway of the tick Ixodes scapularis How XIAP activates the IMD pathway in response to microbial infection remains ill defined. Here, we identified the XIAP enzymatic substrate p47 as a positive regulator of the I. scapularis IMD network. XIAP polyubiquitylates p47 in a lysine 63-dependent manner and interacts with the p47 ubiquitin-like (UBX) module. p47 also binds to Kenny (IKKγ/NEMO), the regulatory subunit of the inhibitor of nuclear factor (NF)- κB kinase complex. Replacement of the amino acid lysine to arginine within the p47 linker region completely abrogated molecular interactions with Kenny. Furthermore, mitigation of p47 transcription levels through RNA interference in I. scapularis limited Kenny accumulation, reduced phosphorylation of IKKβ (IRD5), and impaired cleavage of the NF-κB molecule Relish. Accordingly, disruption of p47 expression increased microbial colonization by the Lyme disease spirochete Borrelia burgdorferi and the rickettsial agent Anaplasma phagocytophilum Collectively, we highlight the importance of ticks for the elucidation of paradigms in arthropod immunology. Manipulating immune signaling cascades within I. scapularis may lead to innovative approaches to reducing the burden of tick-borne diseases.

Keywords: IMD pathway; Lyme disease; rickettsial infections; ticks; ubiquitin ligase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / physiology
  • Anaplasma
  • Animals
  • Arthropod Proteins / metabolism
  • Arthropod Proteins / physiology
  • Borrelia burgdorferi
  • Drosophila
  • Gene Knockout Techniques
  • Ixodes / immunology*
  • Ixodes / microbiology
  • Ixodes / physiology
  • NF-kappa B / metabolism
  • Protein Domains
  • X-Linked Inhibitor of Apoptosis Protein / metabolism
  • X-Linked Inhibitor of Apoptosis Protein / physiology


  • Adaptor Proteins, Signal Transducing
  • Arthropod Proteins
  • NF-kappa B
  • X-Linked Inhibitor of Apoptosis Protein