PACS2 and ME

Endoplasmic reticulum (ER) and mitochondria are tubular organelles with a characteristic “network structure” that facilitates the formation of inter-organellar connections. As a result, mitochondria-associated ER membranes (MAMs), a subdomain of the ER that is tightly linked to and communicates with mitochondria, serve multiple physiological functions including lipid synthesis and exchange, calcium signaling, bioenergetics, and apoptosis. Importantly, emerging evidence suggests that the abnormality and dysfunction of MAMs have been involved in various neurodegenerative disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease (1).

Figure 1: Global view of the architecture/choreography of ER–mitochondria contacts. As depicted, a part of ER tubule and mitochondria form quasi-synaptic structure. Several pairs of integral membrane proteins located on mitochondria and ER important for MERC formation and physical tethering of the organelles were identified, including Mfn1/2 tether, Fis1-Bap31 tether, VAPB-PTPIP51 tether and IP3R-grp75-VDAC1 tripartite complex. The latter is essential for the efficient Ca2+ transfer from the ER to mitochondria. MAM: mitochondria associated ER membrane, OMM = outer mitochondrial membrane, IMM: inner mitochondrial membrane, Mx = matrix, ETC: electron transport chain, TAC: tricarboxylic acid cycle  Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases Transl Neurodegener. 2017;6:21. (ref 1).

Figure 1 shows phosphorin acidic cluster sorting protein 2 (PACS2). PACS2 modulates the Fis1-Bap31 tether (1).

PACS2 is a multifunctionel protein involved in (2): 

• membrane trafficking
• MAM-localized ca2+ signaling
• switching between anabolic and catabolic roles of the MAM
• p53-p21-dependent cell cycle arrest
• apoptosis
• lipid metabolism
• regulating recycling of the metalloproteinase ADAM17
• subcellular distribution of calnexin

PACS2 functions as a metabolic switch that integrates traffic and interorganellar communication with nuclear gene expression in response to anabolic or catabolic cues (2).

Viruses can hijack the PACS2 pathway (2).

The gene PACS2 (TSS1500) is differentially methylated in PBMC from ME patients subtypes (3).

References 

1) LIU and Zhu: Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases.

Transl Neurodegener. 2017; 6: 21.

Published online 2017 Aug 23. doi:  10.1186/s40035-017-0092-6

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567882

2) Thomas et al. Caught in the act - protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease.J Cell Sci. 2017 Jun 1;130(11):1865-1876. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482974/

3)  de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015