2. Academic Validation
  3. CDKI-73 is a Novel Pharmacological Inhibitor of Rab11 Cargo Delivery and Innate Immune Secretion

CDKI-73 is a Novel Pharmacological Inhibitor of Rab11 Cargo Delivery and Innate Immune Secretion

  • Cells. 2020 Feb 5;9(2):372. doi: 10.3390/cells9020372.
Alexandra Sorvina 1,  Tetyana Shandala 1,  Shudong Wang 2,  David J Sharkey 3,  Emma Parkinson-Lawrence 1,  Stavros Selemidis 4,  Douglas A Brooks 1
Affiliations

Affiliations

  • 1 Cell Biology and Disease Research Group, Cancer Research Institute, University of South Australia, Adelaide, SA 5000, Australia.
  • 2 Centre for Drug Discovery and Development, Cancer Research Institute, University of South Australia, Adelaide, SA 5000, Australia.
  • 3 Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
  • 4 School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia.
PMID: 32033486 DOI: 10.3390/cells9020372
Abstract

Innate immunity is critical for host defence against pathogen and environmental challenge and this involves the production and secretion of immune mediators, such as antimicrobial Peptides and pro-inflammatory cytokines. However, when dysregulated, innate immunity can contribute to multifactorial diseases, including inflammatory rheumatic disorders, type 2 diabetes, Cancer, neurodegenerative and cardiovascular diseases and even septic shock. During an innate immune response, antimicrobial Peptides and cytokines are trafficked via Rab11 multivesicular endosomes, and then sorted into Rab11 vesicles for traffic to the plasma membrane and secretion. In this study, a cyclin-dependent kinase inhibitor CDKI-73 was used to determine its effect on the innate immune response, based on previously identified targets for this compound. Our results showed that CDKI-73 inhibited the delivery of Rab11 vesicles to the plasma membrane, resulting in the accumulation of large multivesicular Rab11 endosomes near the cell periphery. In addition to the effect on endosome delivery, CDKI-73 down-regulated the amount of innate immune cargo, including the antimicrobial peptide Drosomycin and pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFα). We concluded that CDKI-73 has the potential to regulate the delivery and secretion of certain innate immune cargo, which could be used to control inflammation.

Keywords

CDKI-73; Drosophila; IL-6; Rab11; TNFα; antimicrobial peptide Drosomycin; endosomes.

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