TENT5C functions as a corepressor in the ligand‐bound glucocorticoid receptor and estrogen receptor α complexes

TL;DR

TENT5C acts as a corepressor for the glucocorticoid and estrogen receptors, influencing their ability to activate genes.

Contribution

TENT5C's role as a corepressor for GR and ERα is identified, with a specific LXXLL motif mediating its interaction with ERα.

Findings

TENT5C represses transcriptional activity of both GR and ERα.

The third LXXLL motif in TENT5C interacts with ERα but not GR.

Mutations in the LXXLL motif disrupt TENT5C's repression of ERα.

Abstract

Terminal nucleotidyltransferase 5C (TENT5C) is a noncanonical poly(A) polymerase that promotes cancer suppression. TENT5C has been proposed to mediate the susceptibility of multiple myeloma to treatment with dexamethasone, a steroid hormone analog that binds to the glucocorticoid receptor (GR). However, the relationship between TENT5C and nuclear receptor (NR) signaling remains unclear. In this study, we investigate the regulatory role of TENT5C in the GR and estrogen receptor α (ERα) ligand complexes. We find that TENT5C acts as a corepressor of both GR and ERα. Molecular dynamics simulations indicate that the third TENT5C LXXLL motif directly interacts with ERα, but not GR. The physical interaction of TENT5C and ERα is supported by co‐immunoprecipitation assays. Reporter assays show that mutations to the third TENT5C LXXLL motif disrupt TENT5C‐mediated repression of ERα but do not affect the repression of the GR complex. In addition, the disruption of TENT5C poly(A) polymerase activity does not appear to affect TENT5C repression of ERα in the cell lines studied. Taken together, our findings highlight a role of TENT5C as an NR corepressor, differentially modulating GR‐ and ERα‐induced transcriptional activity.

TENT5C is a suppressor of ERα and GR transcriptional activation. A specific LXXLL motif in TENT5C, absent in the other members of the TENT5 subfamily, mediates a stable interaction with the Ligand Binding Domain of ERα but not with that of GR. Mutations to the LXXLL motif result in a weaker interaction between TENT5C and ERα and rescue ERα transcriptional activation in a context‐dependent manner.

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