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MTMR3 Risk Allele Enhances Innate Receptor-Induced Signaling and Cytokines by Decreasing Autophagy and Increasing Caspase-1 Activation

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MTMR3 Risk Allele Enhances Innate Receptor-Induced Signaling and Cytokines by Decreasing Autophagy and Increasing Caspase-1 Activation MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation Amit Lahiri, Matija Hedl, and Clara Abraham1 Department of Medicine, Yale University, New Haven, CT 06511 Edited by David Artis, Weill Cornell Medical College, New York, NY, and accepted by the Editorial Board July 10, 2015 (received for review January 27, 2015) Inflammatory bowel disease (IBD) is characterized by dysregulated primary human cells, where responses can be dramatically different host:microbial interactions and cytokine production. Host pattern (8), has not been examined. Given the importance of PRR regu- recognition receptors (PRRs) are critical in regulating these interactions. lation in intestinal tissues and the ability of autophagy to modulate Multiple genetic loci are associated with IBD, but altered functions for PRR-initiated outcomes, we hypothesized that MTMR3 would most, including in the rs713875 MTMR3/HORMAD2/LIF/OSM region, are regulate PRR-induced autophagy and thereby PRR-induced sig- unknown. We identified a previously undefined role for myotubularin- naling and cytokine secretion. We further hypothesized that the related protein 3 (MTMR3) in amplifying PRR-induced cytokine secre- IBD-associated polymorphisms in the MTMR3/HORMAD2/LIF/ tion in human macrophages and defined MTMR3-initiated mechanisms OSM region would modulate these outcomes. contributing to this amplification. MTMR3 decreased PRR-induced In this study, we identified a role for MTMR3 in PRR-initiated phosphatidylinositol 3-phosphate (PtdIns3P) and autophagy levels, responses in primary human macrophages. Upon PRR stimulation, β thereby increasing PRR-induced caspase-1 activation, autocrine IL-1 MTMR3 decreased PtdIns3P levels and autophagy, which in turn κ secretion, NF B signaling, and, ultimately, overall cytokine secretion. increased caspase-1 activation and autocrine IL-1β secretion, PI3K This MTMR3-mediated regulation required the N-terminal pleckstrin and NFκB activation, and secretion of long-term cytokines. The homology-GRAM domain and Cys413 within the phosphatase do- MTMR3-mediated regulation of these PRR-induced outcomes main of MTMR3. In MTMR3-deficient macrophages, reducing the required the pleckstrin homology-Glucosyltransferase, Rab- enhanced autophagy or restoring NFκB signaling rescued PRR- like GTPase activator and Myotubularins (PH-GRAM) domain induced cytokines. Macrophages from rs713875 CC IBD risk carriers demonstrated increased MTMR3 expression and, in turn, decreased and Cys413 within the phosphatase domain of MTMR3. Further, PRR-induced PtdIns3P and autophagy and increased PRR-induced MTMR3 transiently relocalized from the cytoplasm to the nu- caspase-1 activation, signaling, and cytokine secretion. Thus, the cleus after PRR stimulation, corresponding to the PRR-induced P rs713875 IBD risk polymorphism increases MTMR3 expression, which PtdIns3 and autophagy observed in the cytoplasm. Monocyte- modulates PRR-induced outcomes, ultimately leading to enhanced derived macrophages (MDMs) from rs713875 CC genotype PRR-induced cytokines. IBD risk carriers expressed increased MTMR3 mRNA and protein, and, in turn, decreased PRR-induced PtdIns3P and Crohn’s disease | ulcerative colitis | NOD2 | genetics | Toll-like receptors autophagy levels and increased PRR-induced caspase-1 activation, signaling and cytokine secretion relative to G carriers. These MTMR3 nflammatory bowel disease (IBD) is characterized by dysre- results collectively establish a role for the gene in the MTMR3/HORMAD2/LIF/OSM Igulated intestinal immune homeostasis and cytokine production region in association with IBD (1). Given the key role for host–microbe interactions in the in- pathogenesis and highlight a previously undefined mechanism testine, proper regulation of pattern recognition receptor (PRR) for MTMR3 in modulating PRR-induced autophagy and cytokine signaling and cytokine secretion is critical. Although a number of secretion, two processes critical to intestinal immune homeostasis. loci have now been associated with IBD (2), altered functions for the majority of these loci are unknown. Defining these functions is Significance essential to our understanding of IBD pathophysiology and to our ability to ultimately target these implicated pathways. This study describes a previously undefined role for myotubularin- Polymorphisms in the MTMR3/HORMAD2/LIF/OSM region on related protein 3 (MTMR3) in modulating pattern recognition chromosome 22 are associated with Crohn’s disease and ulcerative receptor (PRR)-induced responses and identifies mecha- colitis (2, 3), the two IBD subtypes. The specific gene(s) mediating nisms mediating these outcomes in primary human macro- the association and the functional consequences of the poly- phages. It further defines that MTMR3 in the inflammatory morphisms are not yet reported, although leukemia inhibitory fac- bowel disease risk MTMR3/HORMAD2/LIF/OSM locus accounts tor (LIF)andOncostatinM(OSM) have been proposed as for the genotype-dependent regulation of PRR-initiated out- candidates (2). Myotubularin-related protein 3 (MTMR3) is a comes in macrophages. Our studies highlight mechanisms member of the myotubularin family. Mutations in certain myo- whereby MTMR3 may contribute to intestinal inflammation, tubularin members can lead to neuro-muscular diseases (4). specifically both by inhibiting autophagy and by enhancing Active myotubularin members possess phosphoinositide 3- signaling and cytokine secretion upon stimulation of a broad protein tyrosine phosphatase activity; the active phosphatase do- range of PRRs. main located in the MTMR3 N-terminal region dephosphorylates phosphatidylinositol 3-phosphate (PtdIns3P) and PtdIns(3,5)P2 (4, Author contributions: A.L., M.H., and C.A. designed research; A.L., M.H., and C.A. performed 5). PtdIns3P is an important lipid mediator of membrane traf- research; A.L., M.H., and C.A. analyzed data; and C.A. wrote the paper. ficking and signaling and participates in effector recruitment to The authors declare no conflict of interest. autophagic membranes. Consistently, MTMR3 can inhibit consti- This article is a PNAS Direct Submission. D.A. is a guest editor invited by the Editorial tutive autophagy in select cell lines (5–7). However, MTMR3 bi- Board. ology has been relatively unexplored, and a role for MTMR3 in 1To whom correspondence should be addressed. Email: [email protected]. regulating PRR-initiated outcomes, which are relevant to the in- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. INFLAMMATION IMMUNOLOGY AND testinal immune system, has not been reported. Further, its role in 1073/pnas.1501752112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1501752112 PNAS | August 18, 2015 | vol. 112 | no. 33 | 10461–10466 Downloaded by guest on September 26, 2021 Results IL-1β ABIL-6 x10 *** TNFα Human Myeloid-Derived Cells from IBD Risk-Associated rs713875 CC IL-10 ** ** Carriers Demonstrate Increased PRR-Induced Cytokine Secretion. 3000 0.025 *** 0.020 PRR-initiated outcomes, including cytokine secretion, in myeloid- 2000 0.015 1000 0.010 derived cells are important in IBD pathophysiology (9). As the 0.005 rs713875 MTMR3/HORMAD2/LIF/OSM region polymorphism as- 0 0.000 MTMR3 RNA cytokines (pg/ml) MDP - + + CC CGGG sociated with IBD (3) contains genes with roles in autophagy [e.g., *** MTMR3 (5–7)], which can indirectly modulate cytokine secretion, siRNA scr MTMR3 ** LIF 0.8 and genes regulating T-cell cytokines [e.g., (10)], we questioned C 0.6 if this polymorphism modulates PRR-initiated cytokines. The PRR MTMR3 0.4 nucleotide-binding oligomerization domain 2 (NOD2) is associated GAPDH 0.2 0.0 to Crohn’s disease (1). We therefore used muramyl dipeptide CC CG GG CC CG GG MTMR3 Protein (MDP), the peptidoglycan component that specifically activates NOD2, to treat MDMs from 100 healthy individuals. We ex- Fig. 2. MTMR3 regulates PRR-induced cytokine secretion, and MDMs from amined IL-1β protein secretion, given its role in amplifying cy- rs713875 C IBD risk carriers have increased MTMR3 expression. (A)MDMs(n = 4) β were transfected with scrambled or MTMR3 siRNA for 48 h, then treated with tokines in MDMs (11). IL-1 secretion was normalized to μ + untreated cells, and data were log2 transformed. MDMs from 100 g/mL MDP for 24 h. Mean cytokine secretion SEM. Similar results were β observed for an additional n = 6. (B and C) MDMs from rs713875 CC, CG, or GG rs713875 C risk genotype carriers secreted increased IL-1 upon = A carriers (n 12 per genotype) were assessed for (B) MTMR3 mRNA expression NOD2 stimulation compared with GG carriers (Fig. 1 ). Effects (change in CT value normalized to GAPDH and represented as a linear scale) were most pronounced at low MDP doses, but persisted at + A SEM or (C) protein expression by Western blot. Representative Western blot higher doses (Fig. 1 ). Similar results were observed with tumor from n = 3 per genotype and densitometry summary for the full cohort (nor- necrosis factor (TNF)α secretion (Fig. S1A). malized to GAPDH) + SEM. Scr, scrambled. **P < 0.01; ***P < 0.001. Both the NOD2 ligand peptidoglycan and the TLR2 ligand lipotechoic acid are present in Gram-positive bacteria. MDMs treated with Pam3Cys, a synthetic TLR2 ligand, also showed in- following TLR2, TLR3, TLR4, TLR5, TLR7, and TLR9 stimu- creased IL-1β (Fig. 1B)andTNFα (Fig. S1B) protein secretion. lation. Taken together, myeloid cells from rs713875 IBD risk Cytokine secretion from NOD2- and
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