TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41

Carey, Kimberly L.; Paulus, Geraldine L.C.; Wang, Lingfei; Balce, Dale R.; Luo, Jessica W.; Bergman, Philip S.; Ferder, Ianina C.; Kong, Lingjia; Renaud, Nicole; Singh, Shantanu; Kost‐Alimova, Maria; Nyfeler, Beat; Virgin, Herbert W.; Xavier, Ramnik J.

doi:10.1016/j.celrep.2020.108371

Cited by 28 publications

(31 citation statements)

References 97 publications

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“…We can speculate that CD68 levels increase in NPC samples as a consequence of TFEB activation, analogous to what is observed in HeLa cells overexpressing TFEB. This same study showed that ablation of TFEB impedes CD68 mRNA expression [61]. However, we cannot rule out that the cultures could have some contamination.The method that we used to generate primary hepatocytes includes a centrifugation at low centrifugation speed.…”

Section: Discussionmentioning

confidence: 83%

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Balboa

Marín

Oyarzún

et al. 2021

Cells

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Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

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Section: Discussionmentioning

confidence: 83%

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Balboa

Marín

Oyarzún

et al. 2021

Cells

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“…We then provided evidence for the implication of lysosomes in regulating Erk3 abundance. The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis that is required for autophagy [ 33 ]. Expressing TFEB dramatically reduced Erk3 levels (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Inactivation of EGLN3 hydroxylase facilitates Erk3 degradation via autophagy and impedes lung cancer growth

et al. 2022

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EGLN3 is critically important for growth of various cancers including lung cancer. However, virtually nothing is known about the role and mechanism for EGLN3 hydroxylase activity in cancers. EGLN3 catalyzes the hydroxylation of extracellular signal-regulated kinase 3 (Erk3), a potent driver of cancers. The role and mechanism for EGLN3-induced stabilization of Erk3 remain to be defined. Here, we show that Erk3 interacts with heat shock cognate protein of 70 kDa (HSC70) and lysosome-associated membrane protein type 2 A (LAMP2A), two core components of chaperone-mediated autophagy (CMA). As a consequence, Erk3 is degraded by the CMA-lysosome pathway. EGLN3-catalyzed hydroxylation antagonizes CMA-dependent destruction of Erk3. Mechanistically, hydroxylation blunts the interaction of Erk3 with LAMP2A, thereby blocking lysosomal decay of Erk3. EGLN3 inactivation inhibits macrophage migration, efferocytosis, and M2 polarization. Studies using EGLN3 catalytically inactive knock-in mice indicate that inactivation of EGLN3 hydroxylase in host cells ameliorates LLC cancer growth through reprogramming the tumor microenvironment (TME). Adoptive transfer of macrophages with inactivated EGLN3 restrains tumor growth by mounting anti-tumor immunity and restricting angiogenesis. Administration of EGLN3 hydroxylase pharmacologic inhibitor to mice bearing LLC carcinoma impedes cancer growth by targeting the TME. LLC cells harboring inactivated EGLN3 exhibit reduced tumor burden via mitigating immunosuppressive milieu and inducing cancer senescence. This study provides novel insights into the role of CMA in regulating Erk3 stability and the mechanism behind EGLN3-enhanced stability of Erk3. This work demonstrates that inactivation of EGLN3 in malignant and stromal cells suppresses tumor by orchestrating reciprocal interplays between cancer cells and the TME. This work sheds new light on the role and mechanism for EGLN3 catalytic activity in regulating cancer growth. Manipulating EGLN3 activity holds promise for cancer treatment.

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“…Axl (AXL Receptor Tyrosine Kinase) signalling via its ligand growth arrest gene 6 ( Gas6 ) that is also upregulated after CCI, facilitates phagocytosis of apoptotic cells by microglia as well as increasing cellular migration and myelination and reducing apoptosis and toll-like receptor-mediated inflammation (Gilchrist et al, 2020; Goudarzi et al, 2020; Grommes et al, 2008). Bhlhe40 is a transcription factor that regulates myeloid cell activation and inflammation as well as self-renewal (Carey et al, 2020; Jarjour et al, 2019). There was substantially less overlap when comparing downregulated genes in the MGnD phenotype (25% in males, 24% in female).…”

Section: Discussionmentioning

confidence: 99%

Sex-specific transcriptome of spinal microglia in neuropathic pain due to peripheral nerve injury

Fiore

Yin

Güneykaya

et al. 2021

Preprint

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Recent studies have suggested a sexually dimorphic role of microglia in the maintenance of neuropathic pain in rodents. Here, we utilized RNA sequencing analysis and in vitro primary cultures of microglia to characterize the sex differences in microglia in pain-related regions in nerve injury and chemotherapy-induced peripheral neuropathy mouse models. Whilst mechanical allodynia and behavioral changes were observed in all models, transcriptomic analysis revealed a substantial change in microglial gene expression only within the ipsilateral lumbar spinal cord 7-days after nerve injury. Both sexes upregulated genes associated with inflammation, phagosome, and lysosome activation, though males revealed a prominent global transcriptional shift not observed in female mice, reflecting acute activation. Further, in vitro studies revealed that only male microglia from nerve-injured mice developed a reactive phenotype with increased phagocytotic activity. This study indicates distinct sex differences in spinal microglia and suggests they contribute to the sex-specific pain processing following nerve injury.

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TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41

Cited by 28 publications

References 97 publications

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Inactivation of EGLN3 hydroxylase facilitates Erk3 degradation via autophagy and impedes lung cancer growth

Sex-specific transcriptome of spinal microglia in neuropathic pain due to peripheral nerve injury

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