bioRxiv Science⌕ Search

Biology subjects

Niphakis, M.

Publications and source records attributed to Niphakis, M..

3 recordsLinked to original sources
bioRxiv2025

ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity

Chronic inflammation in autoimmunity is driven by T cell hyperactivation. This unregulated response to self is fuelled by heightened metabolic programmes, which offers a promising new direction to uncover novel treatment strategies. /{beta}-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of -ketoglutarate dehydrogenase (-KGDH), and its expression in CD4+ T cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T cell metabolism and function - and thus, the downstream implication for autoimmunity - is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using a murine model of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T cells and delays the onset of diabetes in vivo. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T cell-mediated autoimmunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/643996v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@bb3fcborg.highwire.dtl.DTLVardef@1594fc8org.highwire.dtl.DTLVardef@84e078org.highwire.dtl.DTLVardef@1ad023e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗
bioRxiv2023

Attenuating ABHD17 enhances S-palmitoylation, membrane localization and signal transduction of NOD2 and Crohn's disease-associated variants.

BACKGROUND AND AIMSNOD2 is an intracellular innate immune receptor that detects bacterial peptidoglycan fragments. Although nominally soluble, some NOD2 is associated with the plasma membrane and endosomal compartments for microbial surveillance. This membrane targeting is achieved through post-translational S- acylation of NOD2 by the protein acyltransferase ZDHHC5. Membrane attachment is necessary to initiate a signaling cascade in response to cytosolic peptidoglycan fragments. Ultimately, this signaling results in the production of antimicrobial peptides and proinflammatory cytokines. In most cases, S-acylation is a reversible post- translational modification with removal of the fatty acyl chain catalyzed by one of several acyl protein thioesterases. Deacylation of NOD2 by such an enzyme will displace it from the plasma membrane and endosomes, thus preventing signaling. METHODSTo identify the enzymes responsible for NOD2 deacylation, we used engineered cell lines with RNA interference and small-molecule inhibitors. These approaches were combined with confocal microscopy, acyl-resin-assisted capture, immunoblotting, and cytokine multiplex assays. RESULTSWe identified /{beta}-hydrolase domain-containing protein 17 isoforms (ABHD17A, ABHD17B, and ABHD17C) as the acyl protein thioesterases responsible for NOD2 deacylation. Inhibiting ABHD17 increased the plasma membrane localization of wild-type NOD2 and a subset of poorly acylated Crohns disease-associated variants. This enhanced NOD2 activity, increasing NF-{kappa}B activation and pro-inflammatory cytokine production in epithelial cells. CONCLUSIONSThese findings demonstrate that ABHD17 isoforms are negative regulators of NOD2. The results also suggest that targeting ABHD17 isoforms could restore functionality to specific Crohns disease-associated NOD2 variants, offering a potential therapeutic strategy. Grant SupportThis work was supported by a Project Grant from the Canadian Institutes of Health Research (grant no.: PJT166010; to G.D.F.), an Innovator Award from the Kenneth Rainin Foundation, and a grant from the National Institutes of Health, (R01CA193994 to B.F.C). A Tier 1 Canada Research Chair supports G.D.F. in Multiomics of Lipids and Innate Immunity. C.L.D. was supported by a Breakthrough Accelerator Fellowship from the Dalhousie Medical Research Foundation/Medical Research Development Office. N.M is a recipient of a graduate scholarship from the I3V Wave and the Dalhousie Medical Research Development Office. DisclosuresThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. SYNOPSISThe peptidoglycan sensor NOD2 requires post-translational S-acylation to associate with cellular membranes and transduce signals. This study identified the ABHD17 family of thioesterases as responsible for NOD2 deacylation and inactivation. Inhibiting or silencing ABHD17 isoforms increases S-acylation and functionality of NOD2 and a subset of Crohns disease-associated variants.

immunology↗
bioRxiv2022

Chemoproteomic identification of a dipeptidyl peptidase 4 (DPP4) homolog in Bacteroides thetaiotaomicron important for envelope integrity and fitness

Serine hydrolases play important roles in signaling and human metabolism, yet little is known about the functions of these enzymes in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human protease dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Functional studies reveal that BT4193 is a true homolog of hDPP4 while the other is misannotated and is a proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and is inhibited by FDA-approved type 2 diabetes drugs that target hDPP4. Loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. Taken together, our findings suggest that serine hydrolases contribute to gut microbiota dynamics and may be off-targets for existing drugs that could cause unintended impact on the microbiota.

microbiology↗