DecodeME genet CCPG1 er involveret i endoplasmatisk retikulum stress

DecodeME artiklen (1) udpegede en række gener, der kan være involveret i ME sygdomsmekanismen. Dette er beskrevet her: DecodeME studiet afslører variationer i DNAet fra ME patienter

Et af generne er CCPG1 - cell cycle progression 1.

DecodeME artiklen oplyser følgende om CCPG1 (1):

"CCPG1 mediates the selective degradation of the endoplasmic reticulum by autophagy (62). This is a host defense mechanism when pathogens infect cells, and its deficiency facilitates viral infection (63)."


Sådan virker CCPG1

Endoplasmatisk retikulum (ER) er et netværk af membraner i vores celler, der er opdelt i en ru del og en glat del. Den ru del er dækket af ribosomer og er involveret i proteinsyntese, modifikation og transport af proteiner. Den glatte del producerer lipider, såsom kolesterol og steroider, og spiller en rolle i afgiftning af skadelige stoffer

Retikulofagi eller ER-fagi er den selektive nedbrydning af dele af det endoplasmatiske retikulum. Herved kan skadede dele af ER'et fjernes fra vores celler. Denne proces spiller en rolle i celle stress responset. 

Når virus inficerer vores celler, anvender de ER til eget brug. Vores celler reagere med ER stress og retikulofagi for at bekæmpe virus.

CCPG1 er én ud af flere receptorer, der styrer retikulofagi. 

Figur 2 fra artiklen Reticulophagy and viral infection viser en skematisk oversigt over nogle retikulofagi receptorer (2):

Figur 4 fra artiklen viser, hvordan ER stress øger transkription af CCPG1 (2):

Kort forklaring til figur 4. Ved ER stress ophobes misfoldede proteiner. Så fjernes HSPA5 fra ERN1. ERN1 aktivere XBP1, som sørger for at MIST1 produceres. Og MIST1 sørger for CCPG1 produceres. 

Hvis der er en variation i ME patienters CCPG1, kan reticulofagi responset været nedsat og evnen til at bekæmpe virus være nedsat.

ER stress i ME sygdomsmekanismen

ER stress er et spændende område i ME forskningen, da det er sat i relation til motionsintolerance. Det er beskrevet i et tidligere blogindlæg:

Årsagen til ME patienters motionsintolerance er fundet

Forfattere bag artiklen om WASF3 og motionsintolerance har også skrevet en artikel om mitokondriedysfunktion:

Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Herfra vil jeg bringe et citat, som viser, at ME forskerne allerede tidligere har tænkt på sammenhængen mellem ME, virus, ER stress, mitokondriedysfunktion og sat det i sammenhæng til WASF3 og motionsintolerance:

"The endoplasmic reticulum is a membranous organelle whose major function is the synthesis of luminal/membrane proteins and their maturation, sorting and delivery. However, the ER apparatus can be usurped by viruses for utilization at different stages of their life cycle such as during viral entry, protein synthesis, replication, assembly and exit from the cell (87). As expected with such extraneous activities, viral infections can disrupt ER homeostasis and stress the system. Interestingly, ER stress has been associated with oxidative stress and the two often coexist in various pathological conditions but the underlying mechanism has remained elusive (13). Our observation that ER stress induces WASF3 through a post-transcriptional mechanism, disrupting mitochondrial function and thereby causing oxidative stress, could provide an explanation for this phenomenon (72, 115). It also suggests that the increased WASF3 in ME/CFS could be part of an immune response to a perceived stimulus."


Så lad os glædes over, at ME puslespilsbrikkerne bliver flere og flere og passer sammen.

Referencer:

1) Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome
https://www.medrxiv.org/content/10.1101/2025.08.06.25333109v1
Genetics Delivery Team, Thibaud Boutin, Andrew D. Bretherick, Joshua J. Dibble, Esther Ewaoluwagbemiga, Emma Northwood, Gemma L. Samms, Veronique Vitart, Project and Cohort Delivery Team, Øyvind Almelid, Tom Baker, Malgorzata Clyde, Anne Connolly, Diana Garcia, Shona M. Kerr, Claire Tripp, Jareth C. Wolfe, Patient and Public Involvement, Jackie Goold, Gemma Hoyes, Sian Leary, Simon J. McGrath, Julie Milton, Anna Redshaw, Jim M. Wilson, Marketing and Communications Team, Helen Baxter, Danielle Boobyer, Claire Dransfield, Daphne Lamirel, Isabel Lewis, Nina Muirhead, Ella Ponting, Charles Shepherd, Alice Turner, University of Edinburgh Team, Sumy V. Baby, Sjoerd Beentjes, John Ireland, Ava Khamseh, Ewan McDowall, David Perry, Joshua Slaughter, Genetic Epidemiology of ME/CFS Consortium, Erik Abner, Cindy G. Boer, Estonian Biobank Research Team, Sarah Finer, Genes & Health Research Team, Hele Haapaniemi, Hanna M. Ollila, Beth Pollack, Judith Rosmalen, Erika Romppanen, Sirine Saafi, Richa Saxena, Nasa Sinnott-Armstrong, Anniina Tervi, Lea Urpa, Jesse Valliere, David A. van Heel, Management Team, Sonya Chowdhury, Andy Devereux-Cooke, Chris P. Ponting
medRxiv 2025.08.06.25333109; doi: https://doi.org/10.1101/2025.08.06.25333109
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

2) Wilson A, McCormick C. Reticulophagy and viral infection. Autophagy. 2025 Jan;21(1):3-20. doi: 10.1080/15548627.2024.2414424. Epub 2024 Oct 23. PMID: 39394962; PMCID: PMC11702952.
https://pubmed.ncbi.nlm.nih.gov/39394962/

3) Syed AM, Karius AK, Ma J, Wang PY, Hwang PM. Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Physiology (Bethesda). 2025 Jul 1;40(4):0. doi: 10.1152/physiol.00056.2024. Epub 2025 Feb 17. PMID: 39960432; PMCID: PMC12151296.
https://pubmed.ncbi.nlm.nih.gov/39960432/