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Activation of the Aspergillus PacC zinc finger transcription factor requires two proteolytic steps.

ABSTRACT: The Aspergillus PacC transcription factor undergoes proteolytic activation in response to alkaline ambient pH. In acidic environments, the 674 residue translation product adopts a 'closed' conformation, protected from activation through intramolecular interactions involving the < or = 150 residue C-terminal domain. pH signalling converts PacC to an accessible conformation enabling processing cleavage within residues 252--254. We demonstrate that activation of PacC requires two sequential proteolytic steps. First, the 'closed' translation product is converted to an accessible, committed intermediate by proteolytic elimination of the C-terminus. This ambient pH-regulated cleavage is required for the final, pH-independent processing reaction and is mediated by a distinct signalling protease (possibly PalB). The signalling protease cleaves PacC between residues 493 and 500, within a conserved 24 residue 'signalling protease box'. Precise deletion or Leu498Ser substitution prevents formation of the committed and processed forms, demonstrating that signalling cleavage is essential for final processing. In contrast, signalling cleavage is not required for processing of the Leu340Ser protein, which lacks interactions preventing processing. In its two-step mechanism, PacC processing can be compared with regulated intramembrane proteolysis.

SUBMITTER: Diez E

PROVIDER: S-EPMC125927 | biostudies-literature | 2002 Mar

REPOSITORIES: biostudies-literature

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Activation of the Aspergillus PacC zinc finger transcription factor requires two proteolytic steps.

Díez Eliecer E Alvaro Josué J Espeso Eduardo A EA Rainbow Lynne L Suárez Teresa T Tilburn Joan J Arst Herbert N HN Peñalva Miguel A MA

The EMBO journal 20020301 6

The Aspergillus PacC transcription factor undergoes proteolytic activation in response to alkaline ambient pH. In acidic environments, the 674 residue translation product adopts a 'closed' conformation, protected from activation through intramolecular interactions involving the < or = 150 residue C-terminal domain. pH signalling converts PacC to an accessible conformation enabling processing cleavage within residues 252--254. We demonstrate that activation of PacC requires two sequential proteol ...[more]

PMID: 11889040

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Project description:Using an established human primary cell culture model, we previously demonstrated that the promyelocytic leukemia zinc finger (PLZF) transcription factor is a direct target of the progesterone receptor (PGR) and is essential for progestin-dependent decidualization of human endometrial stromal cells (HESCs). These in vitro findings were supported by immunohistochemical analysis of human endometrial tissue biopsies, which showed that the strongest immunoreactivity for endometrial PLZF is detected during the progesterone (P4)-dominant secretory phase of the menstrual cycle. While these human studies provided critical clinical support for the important role of PLZF in P4-dependent HESC decidualization, functional validation in vivo was not possible due to the absence of suitable animal models. To address this deficiency, we recently generated a conditional knockout mouse model in which PLZF is ablated in PGR-positive cells of the mouse (Plzf d/d). The Plzf d/d female was phenotypically analyzed using immunoblotting, real-time PCR, and immunohistochemistry. Reproductive function was tested using the timed natural pregnancy model as well as the artificial decidual response assay. Even though ovarian activity is not affected, female Plzf d/d mice exhibit an infertility phenotype due to an inability of the embryo to implant into the Plzf d/d endometrium. Initial cellular and molecular phenotyping investigations reveal that the Plzf d/d endometrium is unable to develop a transient receptive state, which is reflected at the molecular level by a blunted response to P4 exposure with a concomitant unopposed response to 17-β estradiol. In addition to a defect in P4-dependent receptivity, the Plzf d/d endometrium fails to undergo decidualization in response to an artificial decidual stimulus, providing the in vivo validation for our earlier HESC culture findings. Collectively, our new Plzf d/d mouse model underscores the physiological importance of the PLZF transcription factor not only in endometrial stromal cell decidualization but also uterine receptivity, two uterine cellular processes that are indispensable for the establishment of pregnancy.

Dataset Information

Activation of the Aspergillus PacC zinc finger transcription factor requires two proteolytic steps.

Publications

Activation of the Aspergillus PacC zinc finger transcription factor requires two proteolytic steps.

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