Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex

Highlights 42• Proteomic analysis of synapses isolated from Alzheimer's disease and control subject 43 brains identifies over 5,500 proteins in human synapses. 44• In silico analysis reveals region-specific decreases in proteins involved in synaptic 45 and mitochondrial function and increases in proteins involved in neuroimmune 46 signaling and intracellular signaling in AD. 47• The apolipoprotein E4 risk gene is associated with exacerbated changes in synaptic 48 proteins in AD. 49 50 Abstract 51Degeneration of synapses in Alzheimer's disease (AD) strongly correlates with cognitive 52 decline, and synaptic pathology contributes to disease pathophysiology. We recently 53 discovered that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 54 (APOE4), exacerbates synapse loss and synaptic accumulation of oligomeric amyloid beta in 55 human AD brain. To begin to understand the molecular cascades involved in synapse loss in 56 AD and how this is mediated by APOE, and to generate a resource of knowledge of changes 57 in the synaptic proteome in AD, we conducted a proteomic screen and systematic in-silico 58 analysis of synaptoneurosome preparations from temporal and occipital cortices of human 59 AD and control subjects with known APOE gene status. Our analysis identified over 5,500 60 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-61 associated changes in multiple molecular pathways including a decreased abundance in AD 62 of proteins important for synaptic and mitochondrial function and an increased abundance of 63 proteins involved in neuroimmune interactions and intracellular signaling. 64 65

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“…We also selected a protein whose levels was unchanged to use as an internal control (Fig 5, full blots shown in supplementary figure 3). 28…”

Section: Resultsmentioning

confidence: 99%

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Hesse

Hurtado

Jackson

et al. 2019

Preprint

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“…The PGRMC1mediated conferral of responsiveness to steroids like P4 presumably evolved in animals [33]. A complex between PGRMC1, the low density lipoprotein (LDL) receptor (LDLR) and the sigma-2 receptor transmembrane protein 97 (TMEM97) regulates the rapid internalization of LDLR via the membrane trafficking function of PGRMC1 [34], which is clearly an animal invention related to intercellular lipid transport, but related to ancient PGRMC1 steroid biology functions [16].…”

Section: Introductionmentioning

confidence: 99%

PGRMC1 effects on metabolism, genomic mutation and CpG methylation imply crucial roles in animal biology and disease

Thejer

Adhikary

Teakel

et al. 2020

BMC Mol and Cell Biol

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Background: Progesterone receptor membrane component 1 (PGRMC1) is often elevated in cancers, and exists in alternative states of phosphorylation. A motif centered on PGRMC1 Y180 was evolutionarily acquired concurrently with the embryological gastrulation organizer that orchestrates vertebrate tissue differentiation.Results: Here, we show that mutagenic manipulation of PGRMC1 phosphorylation alters cell metabolism, genomic stability, and CpG methylation. Each of several mutants elicited distinct patterns of genomic CpG methylation. Mutation of S57A/Y180/S181A led to increased net hypermethylation, reminiscent of embryonic stem cells. Pathways enrichment analysis suggested modulation of processes related to animal cell differentiation status and tissue identity, as well as cell cycle control and ATM/ATR DNA damage repair regulation. We detected different genomic mutation rates in culture.Conclusions: A companion manuscript shows that these cell states dramatically affect protein abundances, cell and mitochondrial morphology, and glycolytic metabolism. We propose that PGRMC1 phosphorylation status modulates cellular plasticity mechanisms relevant to early embryological tissue differentiation.

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“…Briefly, (the reader is referred to previous reviews) noncomprehensive functions briefly membrane trafficking, P4 responsiveness and steroidogenesis, fertility, lipid transport, neural axon migration, synaptic function, and anti-apoptosis. Its subcellular localization can be cytoplasmic, nuclear/nucleolar, mitochondrial, endoplasmic reticulum, cytoplasmic vesicles, or extracellular (Cahill et al, 2016a;Riad et al, 2018;Ryu et al, 2017). It is involved in cell cycle processes at the G1 checkpoint and during mitosis (Luciano et al, 2010;Luciano and Peluso, 2016;Peluso et al, 2014;Sueldo et al, 2015;Terzaghi et al, 2018;Terzaghi et al, 2016), and elevated PGRMC1 expression has been associated with poor prognosis in multiple types of cancer (Ahmed et al, 2010;Cahill et al, 2016a;Losel et al, 2008;Rohe et al, 2009;Ruan et al, 2017;Shih et al, 2019;Willibald et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

Thejer

Adhikary

Kaur

et al. 2019

Preprint

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Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms. Here, we demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects.Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect.This was associated with increased PI3K/Akt activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/Akt activation. Mutation of Y180F strongly attenuated mouse xenograft tumor growth. An accompanying paper demonstrates altered metabolism, mutation incidence, and epigenetic status in these cells, indicating that PGRMC1 phosphorylation strongly influences cancer biology.

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Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex

Cited by 112 publications

References 39 publications

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

PGRMC1 effects on metabolism, genomic mutation and CpG methylation imply crucial roles in animal biology and disease

PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

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