Scientific Reports (Jan 2024)

Understanding the molecular mechanism of pathogenic variants of BIR2 domain in XIAP-deficient inflammatory bowel disease

  • Juhwan Lee,
  • Kyoung Mi Sim,
  • Mooseok Kang,
  • Hyun Ju Oh,
  • Ho Jung Choi,
  • Yeong Eun Kim,
  • Chan-Gi Pack,
  • Kyunggon Kim,
  • Kyung Mo Kim,
  • Seak Hee Oh,
  • Inki Kim,
  • Iksoo Chang

DOI
https://doi.org/10.1038/s41598-023-50932-5
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 14

Abstract

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Abstract X-linked inhibitor of apoptosis protein (XIAP) deficiency causes refractory inflammatory bowel disease. The XIAP protein plays a pivotal role in the pro-inflammatory response through the nucleotide-binding oligomerization domain-containing signaling pathway that is important in mucosal homeostasis. We analyzed the molecular mechanism of non-synonymous pathogenic variants (PVs) of XIAP BIR2 domain. We generated N-terminally green fluorescent protein-tagged XIAP constructs of representative non-synonymous PVs. Co-immunoprecipitation and fluorescence cross-correlation spectroscopy showed that wild-type XIAP and RIP2 preferentially interacted in live cells, whereas all non-synonymous PV XIAPs failed to interact properly with RIP2. Structural analysis showed that various structural changes by mutations, such as hydrophobic core collapse, Zn-finger loss, and spatial rearrangement, destabilized the two loop structures (174–182 and 205–215) that critically interact with RIP2. Subsequently, it caused a failure of RIP2 ubiquitination and loss of protein deficiency by the auto-ubiquitination of all XIAP mutants. These findings could enhance our understanding of the role of XIAP mutations in XIAP-deficient inflammatory bowel disease and may benefit future therapeutic strategies.