Glutaminase Affects the Transcriptional Activity of Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma) via Direct Interaction

Author(s):Show less -

de Guzzi Cassago, Carolina Aparecida ^[1] ; Dias, Marilia Meira ^[1] ; Pinheiro, Matheus Pinto ^[1] ; Pasquali, Camila Cristina ^[1] ; Silva Bastos, Alliny Cristiny ^{[1, 2]} ; Islam, Zeyaul ^{[1, 3]} ; Consonni, Silvio Roberto ^[4] ; de Oliveira, Juliana Ferreira ^[1] ; Gomes, Emerson Machi ^{[5, 1]} ; Rodrigues Ascencao, Carolline Fernanda ^{[1, 2]} ; Honorato, Rodrigo ^[1] ; Pauletti, Bianca Alves ^[1] ; Indolfo, Nathalia de Carvalho ^[1] ; Ribeiro Filho, Helder Veras ^[1] ; Lopes de Oliveira, Paulo Sergio ^[1] ; Migliorini Figueira, Ana Carolina ^[1] ; Paes Leme, Adriana Franco ^[1] ; Berteli Ambrosio, Andre Luis ^[1] ; Gomes Dias, Sandra Martha ^[1]

Affiliation

^[1] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, BR-13083970 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, UNICAMP, Inst Biol, Grad Program Genet & Mol Biol, BR-13083970 Campinas, SP - Brazil

^[3] Qatar Biomed Res Inst, Doha, Ad Dawhah - Qatar

^[4] Univ Estadual Campinas, Dept Biochem & Tissue Biol, BR-13083872 Campinas, SP - Brazil

^[5] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Bioethanol Sci & Technol Lab CTBE, BR-13083970 Campinas, SP - Brazil

• Document type: Journal article
• Source: BIOCHEMISTRY; v. 57, n. 44, p. 6293-6307, NOV 6 2018.
• Web of Science Citations: 1

Abstract

Phosphate-activated glutaminases catalyze the deamidation of glutamine to glutamate and play key roles in several physiological and pathological processes. In humans, GLS encodes two multidomain splicing isoforms: KGA and GAC. In both isoforms, the canonical glutaminase domain is flanked by an N-terminal region that is folded into an EF-hand-like four-helix bundle. However, the splicing event replaces a well-structured three-repeat ankyrin domain in KGA with a shorter, unordered C-terminal stretch in GAC. The multidomain architecture, which contains putative protein-protein binding motifs, has led to speculation that glutaminases are involved in cellular processes other than glutamine metabolism; in fact, some proteins have been identified as binding partners of KGA and the isoforms of its paralogue gene, GLS2. Here, a yeast two-hybrid assay identified nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) as a new binding partner of the glutaminase. We show that KGA and GAC directly bind PPAR gamma with a low-micromolar dissociation constant; the interaction involves the N-terminal and catalytic domains of glutaminases as well as the ligand-binding domain of the nuclear receptor. The interaction occurs within the nucleus, and by sequestering PPAR gamma from its responsive element DR1, the glutaminases decreased nuclear receptor activity as assessed by a luciferase reporter assay. Altogether, our findings reveal an unexpected glutaminase-binding partner and, for the first time, directly link mitochondrial glutaminases to an unanticipated role in gene regulation. (AU)

• FAPESP's process: 16/22246-0 - PPAR gamma repression mechanism as a target to combat diabetes and obesity
• Grantee: Ana Carolina Migliorini Figueira
• Support type: Regular Research Grants
• FAPESP's process: 14/20673-2 - Biophysical and biochemical studies of the mitochondrial pyruvate carrier (MPC) complex and the glutaminase enzyme bound to novel partners
• Grantee: Andre Luis Berteli Ambrosio
• Support type: Regular Research Grants
• FAPESP's process: 11/10127-2 - Studies of the nuclear location and nuclear receptor interaction of glutaminases
• Grantee: Carolina Aparecida de Guzzi Cassago
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/25832-4 - Metabolic regulation of genetic and epigenetic control of gene expression
• Grantee: Sandra Martha Gomes Dias
• Support type: Regular Research Grants
• FAPESP's process: 11/13981-4 - Understanding the cell signalization pathways that impact on glutaminase activity
• Grantee: Carolline Fernanda Rodrigues Ascenção
• Support type: Scholarships in Brazil - Master
• FAPESP's process: 17/11766-5 - Biophysical and biochemical studies of transmembrane mitochondrial proteins and their implication on the tumor metabolism adaptation process
• Grantee: Andre Luis Berteli Ambrosio
• Support type: Regular Research Grants
• FAPESP's process: 14/19518-2 - Biophysical and structural characterization of the interaction of kidney type glutaminase (KGA) and Peroxisome Proliferator-Activated Receptor gamma (PPARg)
• Grantee: Camila Cristina Pascoal
• Support type: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 10/13992-3 - Biochemical and Cellular Characterization of the Kidney-type Glutaminase in complex with its partners
• Grantee: Emerson Rodrigo Machi Gomes
• Support type: Scholarships in Brazil - Master