PGRMC2

PGRMC2 is an intracellular heme-binding protein that operates as a heme chaperone, trafficking labile signalling heme from mitochondria to the nucleus to control the abundance of heme-responsive transcriptional repressors; loss of PGRMC2 in brown adipose tissue depletes nuclear labile heme, stabilizes Rev-Erbα and BACH1, produces mitochondrial defects, and abolishes adaptive thermogenesis (PMID:31748741). In parallel, PGRMC2 acts as a negative regulator of cell cycle entry in reproductive tissue: it physically associates with PGRMC1 and with G3BP2, localizes to the mitotic spindle, and disruption of these interactions drives G1 entry, while loss of the proteins causes metaphase arrest and apoptosis (PMID:25253729). Together with PGRMC1 and PAQR7 it forms a cytoplasmic complex that mediates the antimitotic action of progesterone independently of the nuclear progesterone receptor (PMID:26203174). PGRMC2 supports steroidogenesis and oocyte maturation, with functional overlap with its paralog PGRMC1 (PMID:31301284, PMID:31536721), and mediates rapid steroid-evoked calcium signalling that sustains cardiac contractile output under hypoxic stress (PMID:40069180). At the maternal-fetal interface and in the endometrium, PGRMC2 shapes decidualization-associated gene programs and trophoblast outgrowth (PMID:38452349), restrains inflammatory signalling while promoting HLA-G expression (PMID:39179795), and supports glandular epithelial proliferation that drives Pten-loss endometrial oncogenesis (PMID:40227710).

1. 2014 High

   Established that PGRMC2 is not a solitary effector but a complex-forming protein that physically restrains cell-cycle entry, defining PGRMC1 and G3BP2 as direct partners and the mitotic spindle as a site of action.

   Evidence Pull-down, colocalization, PLA, siRNA and intracellular antibody perturbation with FUCCI readout in granulosa cells

   PMID:25253729

   Open questions at the time

   • Molecular basis of how the complex suppresses G1 entry not defined
   • Spindle role mechanistically unresolved
   • G3BP2 interaction not placed in a signalling pathway
2. 2015 Medium

   Resolved which receptor system mediates progesterone's antimitotic effect, showing a cytoplasmic PGRMC1/PGRMC2/PAQR7 complex carries this action independently of nuclear PGR.

   Evidence siRNA knockdown of each component plus FUCCI and PLA in human granulosa/luteal cells

   PMID:26203174

   Open questions at the time

   • Direct progesterone binding to the complex not demonstrated
   • Stoichiometry and assembly order of the complex unknown
   • Single-lab finding
3. 2019 High

   Defined a biochemical molecular function for PGRMC2 as an intracellular heme chaperone linking mitochondrial heme to nuclear heme-responsive transcription, explaining a metabolic and mitochondrial phenotype.

   Evidence Adipose-specific knockout mice, nuclear labile heme measurement, Rev-Erbα/BACH1 stability assays, mitochondrial assays, pharmacological activator rescue

   PMID:31748741

   Open questions at the time

   • Structural basis of heme binding/transfer not resolved
   • How heme moves between mitochondria and nucleus mechanistically unclear
   • Relationship between heme-chaperone and cell-cycle/progesterone functions unaddressed
4. 2019 Medium

   Extended PGRMC2 function to vertebrate reproduction, showing it supports ovarian progestin synthesis and oocyte maturation, with paralog redundancy revealed only by double knockout.

   Evidence Zebrafish single and double pgrmc1/2 knockouts, DHP measurement, RT-qPCR, ovulation and oocyte maturation assays

   PMID:31301284 PMID:31536721

   Open questions at the time

   • Direct mechanism linking PGRMC2 to steroidogenic enzyme expression unknown
   • Compensation mechanism between paralogs not defined
   • Cross-species relevance to mammals untested
5. 2024 Medium

   Placed PGRMC2 in maternal-fetal physiology, showing it organizes decidualization gene programs, trophoblast support, inflammation, and HLA-G-mediated immune homeostasis.

   Evidence siRNA knockdown in human endometrial stromal cells with RNA-seq/proteomics/outgrowth assay, and chorion-trophoblast knockout in a microfluidic chorio-decidual chip with RNA-seq and immune assays

   PMID:38452349 PMID:39179795

   Open questions at the time

   • Direct molecular targets driving these transcriptional programs unknown
   • Mechanism connecting PGRMC2 to NF-κB/inflammation not defined
   • In vivo human relevance not established
6. 2025 Medium

   Demonstrated a tissue-specific physiological role in the heart, linking PGRMC2-mediated rapid steroid calcium signalling to maintenance of cardiac contractile output under stress.

   Evidence Cardiomyocyte-specific conditional knockout mice with pressure-volume loop measurement under hypoxic stress

   PMID:40069180

   Open questions at the time

   • Which steroid and which calcium channels are engaged not defined
   • Molecular coupling between PGRMC2 and calcium flux unresolved
   • Single-lab finding
7. 2025 Medium

   Identified PGRMC2 as a pro-proliferative/survival factor in endometrial oncogenesis, showing its deletion attenuates Pten-loss-driven hyperplasia and cancer.

   Evidence Uterine-specific Pgrmc2 deletion in a Pten loss-of-function mouse model with histopathology, proliferation scoring, and survival analysis

   PMID:40227710

   Open questions at the time

   • Mechanistic interaction with the PTEN pathway not defined
   • Whether the effect is cell-autonomous in glandular epithelium unresolved
   • No direct molecular target identified

• How PGRMC2's distinct activities — heme chaperoning, complex-dependent cell-cycle suppression, rapid steroid calcium signalling, and transcriptional program control — are mechanistically unified by a single protein remains unresolved.
• No structural model linking heme binding to membrane-progesterone signalling
• No defined direct downstream effectors outside Rev-Erbα/BACH1
• Relationship between the cell-cycle complex and heme-chaperone roles unknown