Rapid proteasomal elimination of 3-hydroxy-3-methylglutaryl-CoA reductase by interferon-γ in primary macrophages requires endogenous 25-hydroxycholesterol synthesis

Steroids
Hongjin LuPeter Ghazal

Abstract

Interferons (IFNs) play a central role in immunity and emerging evidence suggests that IFN-signalling coordinately regulates sterol biosynthesis in macrophages, via Sterol Regulatory Element-Binding Protein (SREBP) dependent and independent pathways. However, the precise mechanisms and kinetic steps by which IFN controls sterol biosynthesis are as yet not fully understood. Here, we elucidate the molecular circuitry governing how IFN controls the first regulated step in the mevalonate-sterol pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), through the synthesis of 25-Hydroxycholesterol (25-HC) from cholesterol by the IFN-inducible Cholesterol-25-Hydroxylase (CH25H). We show for the first 30-min of IFN stimulation of macrophages the rate of de novo synthesis of the Ch25h transcript is markedly increased but by 120-min becomes transcriptionally curtailed, coincident with induction of the Activating Transcription Factor 3 (ATF3) repressor. We demonstrate ATF3 induction by Toll-like receptors is strictly dependent on IFN-signalling. While the SREBP-pathway dependent rates of de novo transcription of Hmgcr are relatively unchanged in the first 90-min of IFN treatment, we find HMGCR enzyme levels undergo a rapid proteasomal-...Continue Reading

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Citations

Mar 25, 2015·Medical Microbiology and Immunology·Konstantinos KotzamanisPeter Ghazal
Jul 17, 2015·Canadian Journal of Microbiology·Ragunath SingaraveluJohn Paul Pezacki
Apr 17, 2016·Journal of Biomedical Science·Raymond HendersonSteven Watterson
May 8, 2016·The Journal of Steroid Biochemistry and Molecular Biology·Saikou Y BahPeter Ghazal
Oct 7, 2015·Briefings in Bioinformatics·Andrew PartonSteven Watterson
Nov 13, 2020·The Journal of Dermatology·Xia YuZhirong Yao
Mar 16, 2021·Frontiers in Immunology·Mikolaj AdamekDieter Steinhagen

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Methods Mentioned

BETA
ubiquitination
dissection
Protein Assay

Software Mentioned

Matlab
R
Image Studio Lite
Graphpad
Bioconductor
MaSigPro

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