Biology subjects

St-Pierre, J.

Publications and source records attributed to St-Pierre, J..

4 recordsLinked to original sources

bioRxiv2022

Murine macrophage choline metabolism underpins IL-4 polarization and RELMα up-regulation

Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated upregulation of choline transport compared to naive macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELM (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naive or mice infected with intestinal helminths Heligmosomoides polygyrus or Nippostrongylus brasiliensis were treated with the choline kinase inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELM expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus with increased egg burden, but there were no differences in intestinal worm count nor differences in N. brasiliensis parasite burden. Together, these data demonstrate that choline metabolism is required for macrophage RELM induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/510305v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@2f83a3org.highwire.dtl.DTLVardef@16b74b1org.highwire.dtl.DTLVardef@1ba1f8dorg.highwire.dtl.DTLVardef@6da06a_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2018

Cell-autonomous transcriptional mechanism for enhancement of translation capacity in secretory cells

Translation is a basic cellular process and its capacity is adapted to cell function. In particular, secretory cells achieve high protein synthesis levels without triggering the protein stress response. It is unknown how and when translation capacity is increased during differentiation. Here, we show that the transcription factor Creb3l2 is a scaling factor for translation capacity in secretory cells and that it directly binds ~75% of regulatory and effector genes for translation. In parallel with this cell-autonomous mechanism, implementation of the physiological UPR pathway prevents triggering the protein stress response. The pituitary differentiation factor Tpit activates Creb3l2 expression, the Creb3l2-dependent regulatory network as well as the physiological UPR pathway. Thus, Creb3l2 implements high basal translation levels through direct targeting of translation effector genes acting downstream of signaling pathways that otherwise regulate protein synthesis. Expression of Creb3l2 may be a useful means to enhance production of therapeutic proteins.

cell biology↗

bioRxiv2018

PGC-1α regulates mitochondrial calcium homeostasis, SR stress and cell death to mitigate skeletal muscle aging

Age-related impairment of muscle function severely affects the health of an increasing elderly population. While causality and the underlying mechanisms remain poorly understood, exercise is an efficient intervention to blunt these aging effects. We thus investigated the role of the peroxisome proliferator-activated receptor {gamma} coactivator 1 (PGC-1), a potent regulator of mitochondrial function and exercise adaptation, in skeletal muscle during aging. We demonstrate that PGC-1 overexpression improves mitochondrial dynamics and calcium buffering in an estrogen-related receptor (ERR)-dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC-1. As a result, PGC-1 prevents tubular aggregate formation and fiber apoptosis in old muscle. Similarly, the pro-apoptotic effects of ceramide and thapsigargin were blunted by PGC-1 in muscle cells. Accordingly, mice with muscle-specific gain- and loss-of-function of PGC-1 exhibit a delayed and premature aging phenotype, respectively. Together, our data reveal a key protective effect of PGC-1 on muscle function and overall health span in aging.\n\nStatement of significanceThe loss of muscle function in aging results in a massive impairment in life quality, e.g. by reducing motor function, strength, endurance, the ability to perform daily tasks or social interactions. Unfortunately, the mechanistic aspects underlying age-related muscle disorders remain poorly understood and treatments improving the disease are extremely limited. We now show that PGC-1, a transcriptional coactivator, is a key regulator of mitochondrial calcium homeostasis, cellular stress and death, all of which are linked to muscle aging and dysfunction. As a result, inhibition of the age-related decline in muscle PGC-1 considerably reduces aging of muscle and constitutes a promising target to prevent and treat the deterioration of muscle function in the elderly.\n\nAbbreviationsBNIP3, BCL2/Adenovirus E1B 19kDa interacting protein 3; Cpt1b, carnitine palmitoyltransferase 1B; CSQ1, calsequestrin 1; Drp1, dynamin-related protein 1; ER stress, endoplasmic reticulum stress; ERR, estrogen-related receptor ; Fis1, fission 1; GRP75, Glucose-Regulated Protein 75; IGFBP5, insulin like growth factor binding protein 5; IP3, inositol 1,4,5-trisphosphate; IP3R1, inositol 1,4,5-trisphosphate receptor type 1; Letm1, leucine zipper and EF-hand containing transmembrane protein 1; MAMs, mitochondria-associated ER membranes; Mcad, medium-chain acyl-CoA dehydrogenase; Opa1, optic atrophy 1; OXPHOS, oxidative phosphorylation; PGC-1, peroxisome proliferator-activated receptor {gamma} coactivator 1; pH2AX, phospho-H2A Histone Family Member X; ppRB, phospho-preproretinoblastoma-associated protein; Puma, BCL2 Binding Component 3; ROS, reactive oxygen species; SR, sarcoplasmic reticulum; TA, tibialis anterior; TBP, TATA binding protein; TPG, thapsigargin; Ucp3, uncoupling protein 3; VDAC, voltage-dependent anion channel; XBP1, X-Box Binding Protein 1; Xiap, X-linked inhibitor of apoptosis protein

cell biology↗

bioRxiv2017

Translational and HIF1α-dependent metabolic reprograming underpin oncometabolomeplasticity and synergy between oncogenic kinase inhibitors and biguanides.

There is heightened interest to devise therapies that target the oncometabolome. We show that kinase inhibitors (KIs) and biguanides synergistically target melanoma, leukemia, and breast, colon and renal cancer cells, but not non-transformed cells. Metabolic profiling confirmed opposing effects of KIs and biguanides on glycolysis, but this was insufficient to explain the observed synergy between the drugs. Rather, we define a critical role for the synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine as well as reductive glutamine metabolism, in determining the sensitivity of cancer cells to KI - biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating translation of mRNAs encoding PC, ASNS, PHGDH and PSAT1. Ablation of 4E-BP1 and 2 results in a dramatic increase in serine, aspartate and asparagine levels and a substantial decrease in sensitivity of breast cancer and melanoma cells to KI - biguanide combinations. In turn, efficacy of KI - biguanide combinations is impeded by HIF1 and sustained reductive glutamine metabolism. These findings identify hitherto unappreciated translational reprograming of NEAA synthesis and HIF1-dependent stimulation of reductive glutamine metabolism as critical metabolic vulnerabilities of cancer that underpin synergy between KIs and biguanides.

cancer biology↗