DecodeMe Candidate Gene
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.
CHROMOSOME 15
Chr15 contained no Tier 1 genes and one Tier 2 gene.
*********************
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).
****************
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.
