Substrate-inactivated cyclooxygenase-2 is disposed of by exosomes through the ER-Golgi pathway

Esraa Saadi, Sharon Tal, Liza Barki-Harrington

Research output: Contribution to journalArticlepeer-review

Abstract

Catalysis of arachidonic acid (AA) by cyclooxygenase-2 (COX-2) gives rise to a single product that serves as a precursor for all prostaglandins, which are central mediators of inflammation. Rapid up-regulation of COX-2 expression in response to pro-inflammatory stimuli is a well-characterized means of generating the large pool of prostaglandins necessary for inflammation. However, an efficient inflammatory process must also terminate rapidly and thus requires cessation of COX-2 enzymatic activity and removal of excess protein from the cell. Previous studies showed that COX-2 that has not been exposed to AA ('naive') degrades in the cellular proteasome. However, continuous exposure to AA induces suicide inactivation of COX-2 and its elimination no longer occurs in neither the proteasomal nor lysosomal machineries. In the present study, we show that either overexpressed or endogenously induced COX-2 is secreted via exosomes through the endoplasmic reticulum-Golgi pathway. We further find that excretion of COX-2 is significantly enhanced by prolonged exposure to AA. Genetic or chemical inhibition of COX- 2 enzymatic activity has no effect on its secretion in the absence of substrate, but prevents the additional activity-dependent secretion. Finally, transfer of COX-2 to target cells only occurs in the absence of AA stimulation. Together, these results suggest that exosomal secretion of AA-activated COX-2 constitutes a means to remove damaged inactive COX-2 from the cell.

Original languageEnglish
Pages (from-to)3141-3151
Number of pages11
JournalBiochemical Journal
Volume475
Issue number19
DOIs
StatePublished - 12 Oct 2018

Bibliographical note

Funding Information:
This work was supported by the Israel Science Foundation [grant no. 1445/14 to L.B.H.].

Publisher Copyright:
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Substrate-inactivated cyclooxygenase-2 is disposed of by exosomes through the ER-Golgi pathway'. Together they form a unique fingerprint.

Cite this