I'm not going to pretend I understand all of this.. but it's clear that we are talking about an essential biological process that affects every cell in the body.
This is behind a paywall, but it confirms my line of thought...
Trends Sig-1R occurs specifically at the MAM, the interface between the ER and mitochondria, where it promotes cellular survival. Upon stimulation by agonists or stressors, Sig-1R can translocate to the PM to interact with ion channels, receptors, and kinases. Experimental and bioinformatics studies have identified interactions between Sig-1R and other functional proteins in the PM, ER, mitochondria, and even the cytosol. CNS diseases have been reported to relate to Sig-1R, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, stroke/ischemia, pain/neuropathic pain, and certain psychiatric disorders. Pharmacological or cellular engineering targeting Sig-1R may provide therapeutic opportunities to treat such diseases. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein that resides specifically in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), an interface between ER and mitochondria. In addition to being able to translocate to the plasma membrane (PM) to interact with ion channels and other receptors, Sig-1R also occurs at the nuclear envelope, where it recruits chromatin-remodeling factors to affect the transcription of genes. Sig-1Rs have also been reported to interact with other membranous or soluble proteins at other loci, including the cytosol, and to be involved in several central nervous system (CNS) diseases. Here, we propose that Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in living systems. Keywords sigma-1 receptor pluripotent modulator diseases
What Is Cytosol? How Is It Different From Cytoplasm? » Science ABC https://www.scienceabc.com › Pure Sciences Cytosol is the fluid that's found inside living cells. More specifically, it's the water-based fluid in which organelles, proteins and other structures of the cell live. Also known as the cytoplasmic matrix, it constitutes most of the intracellular fluid (ICF).
This postulates that the Sigma1 interacts with the cell not only at the sites that fold proteins(Alzheimer's) but in the cellular fluid.
This would bring in the interleukins. All of this is cutting edge research, the interleukins are still being defined, so of course there is little research on how the Sigma1 controls them, but some of it is starting to emerge.
Mechanism of Action and Applications of Interleukin 24 in Immunotherapy Leah Persaud,1,2 Dayenny De Jesus,1 Oliver Brannigan,1 Maria Richiez-Paredes,1 Jeannette Huaman,2,3 Giselle Alvarado,1 Linda Riker,1 Gissete Mendez,1 Jordan Dejoie,1 and Moira Sauane1,2,* Anthony Lemarié, Academic Editor Author information Article notes Copyright and License information Disclaimer This article has been cited by other articles in PMC. Go to: Abstract Interleukin 24 (IL-24) is an important pleiotropic immunoregulatory cytokine, whose gene is located in human chromosome 1q32-33. IL-24’s signaling pathways have diverse biological functions related to cell differentiation, proliferation, development, apoptosis, and inflammation, placing it at the center of an active area of research. IL-24 is well known for its apoptotic effect in cancer cells while having no such effect on normal cells. IL-24 can also be secreted by both immune and non-immune cells. Downstream effects of IL-24, after binding to the IL-20 receptor, can occur dependently or independently of the JAK/STAT signal transduction pathway, which is classically involved in cytokine-mediated activities. After exogenous addition of IL-24, apoptosis is induced in tumor cells independently of the JAK/STAT pathway. We have shown that IL-24 binds to Sigma 1 Receptor and this event induces endoplasmic reticulum stress, calcium mobilization, reactive oxygen species generation, p38MAPK activity, and ceramide production. Here we review IL-24’s role in autoimmunity, infectious disease response, wound repair, and vascular disease. Detailed understanding of the pleiotropic roles of IL-24 signaling can assist in the selection of more accurate therapeutic approaches, as well as targeting of appropriate cell types in treatment strategy development, and ultimately achieve desired therapeutic effects.
Go to: ABSTRACT Interleukin 24 (IL-24) is a new member of the IL-10 family of cytokines and it signals through two heterodimeric receptors: IL-20R1/IL-20R2 and IL-22R1/IL-20R2. Upon binding to its receptors, IL-24 induces rapid activation of Stat-1 and Stat-3 transcription factors, which appear to play a role in cell survival and proliferation. Under physiological conditions, the major sources of IL-24 are the activated monocytes and T helper 2 cells, whereas the major IL-24 target tissues, based on the receptor expression pattern, are non-haematopoietic in origin, and include skin, lung and reproductive tissues. Structurally and functionally, IL-24 is highly conserved across species. This review highlights our current knowledge of IL-24 as a cytokine, with much less emphasis placed on the non-receptor-mediated functions (a subject of several reviews) focused on in much of the earlier literature on IL-24. The potential roles of IL-24 as part of a complex cytokine network in wound healing, psoriasis and cancer are discussed.
Role of IL-33 in inflammation and disease Ashley M Millercorresponding author1 Author information Article notes Copyright and License information Disclaimer This article has been cited by other articles in PMC. Go to: Abstract Interleukin (IL)-33 is a new member of the IL-1 superfamily of cytokines that is expressed by mainly stromal cells, such as epithelial and endothelial cells, and its expression is upregulated following pro-inflammatory stimulation. IL-33 can function both as a traditional cytokine and as a nuclear factor regulating gene transcription. It is thought to function as an 'alarmin' released following cell necrosis to alerting the immune system to tissue damage or stress. It mediates its biological effects via interaction with the receptors ST2 (IL-1RL1) and IL-1 receptor accessory protein (IL-1RAcP), both of which are widely expressed, particularly by innate immune cells and T helper 2 (Th2) cells. IL-33 strongly induces Th2 cytokine production from these cells and can promote the pathogenesis of Th2-related disease such as asthma, atopic dermatitis and anaphylaxis. However, IL-33 has shown various protective effects in cardiovascular diseases such as atherosclerosis, obesity, type 2 diabetes and cardiac remodeling. Thus, the effects of IL-33 are either pro- or anti-inflammatory depending on the disease and the model. In this review the role of IL-33 in the inflammation of several disease pathologies will be discussed, with particular emphasis on recent advances.
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IL-33 appears to be a cytokine with dual function, acting both as a traditional cytokine through activation of the ST2L receptor complex and as an intracellular nuclear factor with transcriptional regulatory properties [10]. The amino terminus of the IL-33 molecule contains a nuclear localization signal and a homeodomain (helix-turn-helix-like motif) that can bind to heterochromatin in the nucleus and has similar structure to the Drosophila transcription factor engrailed [2,11]. In a similar manner to which a motif found in Kaposi sarcoma herpesvirus LANA (latency-associated nuclear antigen) attaches its viral genomes to mitotic chromosomes, nuclear IL-33 is thought to be involved in transcriptional repression by binding to the H2A-H2B acidic pocket of nucleosomes and regulating chromatin compaction by promoting nucleosome-nucleosome interactions [12]. However, the specific transcriptional targets or the biological effects of nuclear IL-33 are unclear at present.
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