Genetics: CCPG1

Hutan

Hutan

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Staff member
DecodeMe Candidate Gene

In DecodeME, we attempted to link GWAS variants to target genes. Here we discuss the top two tiers of predicted linked genes that we are most confident about –‘Tier 1’ and ’Tier 2’.

We defined genes as Tier 1 genes if: (i) they are protein-coding genes, (ii) they have GTEx-v10 expression quantitative trait loci (eQTLs) lying within one of the FUMA-defined ME/CFS-associated intervals, and (iii) their expression and ME/CFS risk are predicted to share a single causal variant with a posterior probability for colocalisation (H4) of at least 75%. For this definition, we disregarded the histone genes in the chr6p22.2 HIST1 cluster, as their sequences and functions are highly redundant (1). This prioritisation step yielded 29 Tier 1 genes.

For the intervals without Tier 1 genes, three Tier 2 genes were defined as the closest protein-coding genes without eQTL association: FBXL4 (chr6q16.1), OLFM4 (chr13q14.3), and CCPG1 (chr15q21.3).
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CHROMOSOME 15
Chr15 contained no Tier 1 genes and one Tier 2 gene.

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CCPG1 (Tier 2)

• Protein: Cell cycle progression 1. UniProt. GeneCards.

• Molecular function: Involved in positive regulation of cell cycle and positive regulation of cell population proliferation. Type II single-pass transmembrane protein. Acts as an assembly platform for Rho protein signalling complexes. Limits guanine nucleotide exchange activity of MCF2L toward RHOA. CCPG1 is a reticulophagy (ER-phagy) receptor. It binds GABARAP (an ATG8-family member) which also binds the gamma-2 subunit of the GABAA receptor, and promotes trafficking of these receptors and their clustering at synapses.

• Cellular function: CCPG1 is an ER-resident protein that acts as an ER stress- and/or unfolded protein response-inducible ER-phagy cargo receptor. It facilitates ER-phagy, via binding to core autophagy proteins, ATG8 and FIP200. CCPG1 protects against ER luminal protein aggregation and consequent unfolded protein response hyperactivation and tissue injury of the exocrine pancreas (57).

• Link to disease: Other autophagy genes, but not CCPG1, are proposed to be mutated in human disease (58). ER-phagy is a host defense mechanism when pathogens infect cells, and its deficiency facilitates viral infection (59).

• Potential relevance to ME/CFS: Potentially in host resistance to infection and/or as an anti-inflammatory factor. ATG13 recruits ULK1, RB1CC1, and ATG101 to the ULK1 complex, essential for initiating and then regulating autophagy. ATG8 is conjugated to the phosphatidylethanolamine (PE) lipid, which then becomes incorporated into the autophagosomal membrane. CCPG1 interacts with all ULK1 complex members in A549 cells (57). ATG13 was strongly upregulated in a study of serum samples of ME/CFS patients (60). Autophagy is inherently anti-inflammatory, as its effects are to remove microbes, damaged organelles, or protein aggregates that otherwise evoke inflammatory signals (61).

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References

57 Smith MD, Harley ME, Kemp AJ, Wills J, Lee M, Arends M, et al. CCPG1 Is a Non-canonical Autophagy Cargo Receptor Essential for ER-Phagy and Pancreatic ER Proteostasis. Dev Cell. 2018 Jan 22;44(2):217-232.e11.

58 Yamamoto H, Zhang S, Mizushima N. Autophagy genes in biology and disease. Nat Rev Genet.2023 Jun;24(6):382–400.

59 Li J, Gao E, Xu C, Wang H, Wei Y. ER-Phagy and Microbial Infection. Front Cell Dev Biol. 2021;9:771353.

60 Gottschalk G, Peterson D, Knox K, Maynard M, Whelan RJ, Roy A. Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE). Mol Cell Neurosci. 2022 May;120:103731.
Forum thread

61 Deretic V. Autophagy in inflammation, infection, and immunometabolism. Immunity. 2021Mar 9;54(3):437–53.
 
See also
InitialConditions

Thread 'Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle‑serving nerves and spinal cord, 2025, Drosen et al.'

Abstract
Chronic muscle fatigue is a condition characterized by debilitating muscle weakness and pain. Based on our recent finding to study the potential effect of mTOR on ATG13 inactivation in chronic muscle fatigue, we report that biweekly oral administration with MHY1485, a potent inducer of mTOR, develops chronic illness in mice resulting in severe muscle weakness. As a mechanism, we observed that MHY1485 feeding impaired ATG13-dependent autophagy, caused the infiltration of inflammatory M1 macrophages (Mφ), upregulated IL6 and RANTES by STAT3 activation, and augmented...
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although note that that paper relates to inactivation of ATG13 and it's unclear how that relates to increased serum levels of ATG13.
 
My guess is that cell cycle is a red herring - most of the information is about autophagy and innate clearance mechanisms anyway. Again, my guess is that this is a gene involved in housekeeping cell junk handling.

I am getting this picture of supervisor hypothalamic microglia nagging the neurons about what a terrible state all the properties the cleaning staff visit out there in the body are in and producing debris to prove it, when if you look at the supervisor's office it is just as bad and for the same underlying reason.

That may be complete nonsense of course but I am trying to account for all these genes somehow!
 
V.R.T. said:
Could you possibly expand on this a little? You've mentioned this idea before but I can't get my head around it.
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We can't get our heads around it either much. Suggestions of TGF beta being up is one thing. And the immune system seems to be busy but without any inflammation to see. Other things in Jo's CD24 story fit with this but I forget the detail.
 
Jonathan Edwards said:
Note that anti-inflammatory creeps in. Jo Cambridge keeps telling me ME/CFS is anti-inflammatory.
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Jonathan Edwards said:
And the immune system seems to be busy but without any inflammation to see.
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As in, it'd be normal to see inflammation markers rising and falling according to various factors, and there's less of it in ME/CFS?

I wondered if it could mean a boot was coming down heavily on processes that don't warrant a strong response, or an ongoing one. Probably not, though.
 
Kitty said:
As in, it'd be normal to see inflammation markers rising and falling according to various factors, and there's less of it in ME/CFS?
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Not so much that. People with ME/CFS have ordinary amounts of inflammation when appropriate as far as I know. But the illness itself seems to involve signals that put the immune system on 'yellow alert' and stop people going for a paddle in the sea.
 
Jonathan Edwards said:
I am getting this picture of supervisor hypothalamic microglia nagging the neurons about what a terrible state all the properties the cleaning staff visit out there in the body are in and producing debris to prove it, when if you look at the supervisor's office it is just as bad and for the same underlying reason.
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Are the supervisors able to initiate interventions if they think it’s necessary? So it’s kind of an issue with the tuning of the decision making process of the supervisors?

And what about the debris from the rest of the body, is that supposed to be there or is it being brought in through some kind of faulty process?
 
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