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Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels.

ABSTRACT: Lysosomes influence dynamic cellular processes such as nutrient sensing and transcriptional regulation. To explore novel transcriptional pathways regulated by lysosomes, we performed microarray analysis followed by qPCR validation in a mouse hepatocyte cell line, AML12, treated with bafilomycin A1 (lysosomal v-type H+-translocating ATPase inhibitor). Pathway enrichment analysis revealed significant downregulation of gene sets related to peroxisomal biogenesis and peroxisomal lipid oxidation upon lysosomal inhibition. Mechanistically, pharmacological inhibition of lysosomes as well as genetic knockdown of Tfeb led to downregulation of the peroxisomal master regulator PPARA and its coactivator PPARGC1A/PGC1?. Consistently, ectopic induction of PPARA transcriptional activity rescues the effects of lysosomal inhibition on peroxisomal gene expression. Collectively, our results uncover a novel metabolic regulation of peroxisomes by lysosomes via PPARA-PPARGC1A transcriptional signalling. Abbreviations: Acox1: acyl-Coenzyme A oxidase 1, palmitoyl; Acot: acyl-CoA thioesterase; ACAA: acetyl-Coenzyme A acyltransferase; ABCD3/PMP70: ATP-binding cassette, sub-family D (ALD), member 3; BafA1: bafilomycin A1; Crot: carnitine O-octanoyltransferase; CTSB: cathepsin B; Decr2: 2-4-dienoyl-Coenzyme A reductase 2, peroxisomal; Ech1: enoyl coenzyme A hydratase 1, peroxisomal; Ehhadh: enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase; FDR: false discovery rate; Hsd17b4: hydroxysteroid (17-beta) dehydrogenase 4; NES: normalized enrichment score; NOM: nominal; Pex: peroxin; PPARA: peroxisome proliferator activated receptor alpha; PPARGC1A: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; TFEB: transcription factor EB.

SUBMITTER: Siong Tan HW

PROVIDER: S-EPMC6613898 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels.

Tan Hayden Weng Siong HWS Anjum B B Shen Han-Ming HM Ghosh Sujoy S Yen Paul M PM Sinha Rohit A RA

Autophagy 20190428 8

Lysosomes influence dynamic cellular processes such as nutrient sensing and transcriptional regulation. To explore novel transcriptional pathways regulated by lysosomes, we performed microarray analysis followed by qPCR validation in a mouse hepatocyte cell line, AML12, treated with bafilomycin A<sub>1</sub> (lysosomal v-type H<sup>+</sup>-translocating ATPase inhibitor). Pathway enrichment analysis revealed significant downregulation of gene sets related to peroxisomal biogenesis and peroxisoma ...[more]

PMID: 31032705

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Project description:Epstein-Barr virus (EBV) nuclear oncoprotein EBNA3C is essential for B-cell transformation and development of several B-cell lymphomas particularly those are generated in an immuno-compromised background. EBNA3C recruits ubiquitin-proteasome machinery for deregulating multiple cellular oncoproteins and tumor suppressor proteins. Although EBNA3C is found to be ubiquitinated at its N-terminal region and interacts with 20S proteasome, the viral protein is surprisingly stable in growing B-lymphocytes. EBNA3C can also circumvent autophagy-lysosomal mediated protein degradation and subsequent antigen presentation for T-cell recognition. Recently, we have shown that EBNA3C enhances autophagy, which serve as a prerequisite for B-cell survival particularly under growth deprivation conditions. We now demonstrate that proteasomal inhibition by MG132 induces EBNA3C degradation both in EBV transformed B-lymphocytes and ectopic-expression systems. Interestingly, MG132 treatment promotes degradation of two EBNA3 family oncoproteins-EBNA3A and EBNA3C, but not the viral tumor suppressor protein EBNA3B. EBNA3C degradation induced by proteasomal inhibition is partially blocked when autophagy-lysosomal pathway is inhibited. In response to proteasomal inhibition, EBNA3C is predominantly K63-linked polyubiquitinated, colocalized with the autophagy-lysosomal fraction in the cytoplasm and participated within p62-LC3B complex, which facilitates autophagy-mediated degradation. We further show that the degradation signal is present at the first 50 residues of the N-terminal region of EBNA3C. Proteasomal inhibition reduces the colony formation ability of this important viral oncoprotein, induces apoptotic cell death and increases transcriptional activation of both latent and lytic gene expression which further promotes viral reactivation from EBV transformed B-lymphocytes. Altogether, this study offers rationale to use proteasome inhibitors as potential therapeutic strategy against multiple EBV associated B-cell lymphomas, where EBNA3C is expressed.

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Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels.

Publications

Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels.

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