ArticleFree radical biology & medicine2018
Hsp90 inhibition renders iNOS aggregation and the clearance of iNOS aggregates by proteasomes requires SPSB2.
Article in Free radical biology & medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 13 citations in OpenAlex.
- UBE2C-TRIM21-driven NOS2 degradation stabilizes Tregs and suppresses pyroptotic signaling in thyrocytes in Hashimoto's thyroiditis.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Regulation of Inducible Nitric Oxide Synthase (NOS2) Expression in Healthy and Inflamed Bowel: A Narrative Review.International journal of molecular sciences · 2026Review
- Ischemia/reperfusion-associated oxidative stress is an aggravating factor for pressure ulcers.Journal of clinical biochemistry and nutrition · 2025Article
- Lithospermic acid targeting heat shock protein 90 attenuates LPS-induced inflammatory response via NF-кB signalling pathway in BV2 microglial cells.Immunologic research · 2025Article
- Subtle Structural Differences Affect the Inhibitory Potency of RGD-Containing Cyclic Peptide Inhibitors Targeting SPSB Proteins.International journal of molecular sciences · 2024Article
- Involvement of Nitric Oxide in Protecting against Radical Species and Autoregulation of M1-Polarized Macrophages through Metabolic Remodeling.Molecules (Basel, Switzerland) · 2023Review
- Molecular and phenotypic distinctions of macrophages in tolerant and susceptible to hypoxia rats.PeerJ · 2023Article
- Role of the PGE2 receptor in ischemia-reperfusion injury of the rat retina.Molecular vision · 2020Article
- Article
- Crystal structure of the SPRY domain of human SPSB2 in the apo state.Acta crystallographica. Section F, Structural biology communications · 2019Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Inducible nitric oxide synthase (iNOS) plays important roles in cell injury and host defense. Our early study demonstrated that heat shock protein 90 (Hsp90) interacts with iNOS and this interaction enhances iNOS function. Recently, we reported that Hsp90 is also essential for iNOS gene transactivation. In the present study, we investigate the role of Hsp90 in controlling iNOS protein stability. In mouse macrophages, Hsp90 inhibition dissociated Hsp90 from iNOS and the latter subsequently formed aggregates. Aggregation deactivated iNOS. iNOS aggregates were cleared by the ubiquitin-proteasome system (UPS) inside cells. CHIP, an Hsp90-dependent E3 ligase, was previously implicated in iNOS turnover. However, CHIP knockdown had little effect on iNOS degradation in Hsp90-inhibited cells, indicating that other E3 ligases accounted for the clearance of iNOS aggregates. Further studies revealed that the SPRY domain-containing SOCS box protein 2 (SPSB2), an E3 ligase-recruiting protein, was essential for the ubiquitination of iNOS aggregates. SPSB2 knockdown or deleting the SPSB2-interacting domain on iNOS prevented the clearance of iNOS aggregates in Hsp90-inhibited cells. Thus, besides modulating iNOS function and gene transcription, Hsp90 is also essential for the protein stability of iNOS. Hsp90 blockade induces iNOS aggregation and SPSB2 is required for UPS degradation of iNOS aggregates.
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