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 γ (PPARγ) as a new binding partner of the glutaminase.
We show that KGA and GAC directly bind PPARγ 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 PPARγ 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.
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