The “switch” that keeps the immune system from attacking the body - EPFL
A Machine for Testing Golf Drivers - William Heath-Robinson
This is also a characteristic of systems 'designed' by a mindless natural process with no power or mechanism for scrapping a suboptimal design and starting again and no ability to predict the future and design for problems which will arise later.
In fact, what creationists think is evidence of a supreme intelligence, more often seems to resemble the designs of the British cartoonist and eccentric designer, William Heath-Robinson, who was famous for his machines designed to solve every-day problem, which were invariably far more complex than they need have been, and which incorporated everyday objects such as umbrellas, full coal-scuttles for counter-weights, lengths of knotted string and stepladders balanced on upright pianos to give them enough height. Take away any of these unlikely components and the whole machine would fail, in an almost perfect metaphor for how evolution can exapt pre-exiting structures from other processes and structures for novel functions, to give the appearance of irreducible complexity.
And yet they work, or at least look as though they would if anyone ever made one.
An example of a Heath-Robinson machine in mammalian 'design' was revealed by a scientists working at the Swiss École polytechnique fédérale de Lausanne (EPFL), who have discovered how the body prevents the immune system from attacking itself.
But, as the very many auto-immune diseases show, this system is far from perfect and frequently fails, sometime with serious, even fatal, consequences.
But the whole immune system is only needed because something designed pathogens such as bacteria, viruses and other parasites, apparently to attack us and make us sick in the first place. Parasites are a source of conflict for creationists who have to believe both that the putative designer god is the only entity capable of designing living things, and that something else created parasites because their god wouldn't do such a thing, and both that their god is omnipotent, but powerless against that other designer.
So, what is this mechanism the EPFL researchers have discovered?
Their findings are the subject of an open access paper in Nature and is explained in an EPFL news release:
The “switch” that keeps the immune system from attacking the bodyMore details of this Heath-Robinson machine that creationists believe is evidence of a supreme intelligence at work, can be read in the team's open access paper in Nature:
Scientists at EPFL uncover the mechanism by which cells mark the protein cGAS for degradation, which is critical in preventing the immune system from mistakenly attacking the body's own tissues.
A microscopic battle rages in our bodies, as our cells constantly fend off invaders through our immune system, a complex system of cells and proteins designed to protect us from harmful pathogens. One of its central components is the enzyme cyclic GMP-AMP synthase (cGAS), which acts as a sentinel, detecting foreign DNA and initiating an immune response.
However, the immune system requires precise regulation to prevent cGAS from mistakenly attacking the body's own tissues, leading to autoimmune disorders, which now affect about 10% of the global population.
Previous studies have revealed a little of how this happens. During cell division – mitosis – the membrane that protects the cell’s nucleus, the nuclear envelope, breaks down and cGAS quickly relocates into the nucleus. There, it attaches itself to nucleosomes – the basic structural unit of DNA packaging in the cell – and becomes covered by another protein called BAF.
All this ensures that cGAS stays inactive and fixed in place, and does not mistakenly interact with the cell's own DNA. It represents a sophisticated balance between immune readiness and protecting the integrity of the cell’s genome. The question is, how does the cell coordinate this with its other everyday functions?
A new study from the group of Andrea Ablasser at EPFL sheds light on how cGAS is regulated, especially during the critical phase of cell division known as mitosis. The study is published in Nature.
The team used advanced imaging and molecular techniques to observe how cGAS is selectively broken down in the nucleus, preventing it from mistakenly responding to the cell's own DNA. They found that the process is mediated by a protein complex known as CRL5–SPSB3, which recognizes a specific motif in cGAS and tags it in the nucleus for destruction. Using structural biology, biochemistry, and cell biology, the researchers visualized the interactions between cGAS and the protein complex at the atomic level.
Specifically, CRL5–SPSB3 adds a protein called ubiquitin to cGAS. Ubiquitin – as the name suggests – is found ubiquitously across eukaryotic cells and one of its functions is to mark other proteins for death. The ubiquitination of cGAS also marks it for destruction, effectively inactivating the sentinel once the threat of an invader has been neutralized.
By elucidating the structure of the cGAS-SPSB3 complex, the study maps out how cGAS is regulated within the nucleus of cells, highlighting the sophistication of the immune system`s regulatory networks.
The implications also extend beyond basic science, allowing scientists to explore new strategies for treating diseases where the immune system is either overactive, such as in autoimmune diseases, or underactive, as in cases of chronic infections or cancer. For example, modulating cGAS activity could potentially enhance the effectiveness of cancer immunotherapies or provide new approaches to preventing autoimmune conditions.
AbstractTo summarise, then. The problem arises because the membrane that separates the DNA in the nucleus from the rest of the cell contains the enzyme, cyclic GMP-AMP synthase (cGAS), whose job is to recognise extra-nuclear DNA and prevent it entering the nucleus. But, when the membrane is broken down, as it has to be during cell replication or mitosis, cGAS is freed and would attack the cell's own DNA if it were left alone. So, another layer of complexity is there to pounce on the free cGAS and neutralise it.
Cyclic GMP-AMP synthase (cGAS) senses aberrant DNA during infection, cancer and inflammatory disease, and initiates potent innate immune responses through the synthesis of 2′3′-cyclic GMP-AMP (cGAMP)1,2,3,4,5,6,7. The indiscriminate activity of cGAS towards DNA demands tight regulatory mechanisms that are necessary to maintain cell and tissue homeostasis under normal conditions. Inside the cell nucleus, anchoring to nucleosomes and competition with chromatin architectural proteins jointly prohibit cGAS activation by genomic DNA8,9,10,11,12,13,14,15. However, the fate of nuclear cGAS and its role in cell physiology remains unclear. Here we show that the ubiquitin proteasomal system (UPS) degrades nuclear cGAS in cycling cells. We identify SPSB3 as the cGAS-targeting substrate receptor that associates with the cullin–RING ubiquitin ligase 5 (CRL5) complex to ligate ubiquitin onto nuclear cGAS. A cryo-electron microscopy structure of nucleosome-bound cGAS in a complex with SPSB3 reveals a highly conserved Asn-Asn (NN) minimal degron motif at the C terminus of cGAS that directs SPSB3 recruitment, ubiquitylation and cGAS protein stability. Interference with SPSB3-regulated nuclear cGAS degradation primes cells for type I interferon signalling, conferring heightened protection against infection by DNA viruses. Our research defines protein degradation as a determinant of cGAS regulation in the nucleus and provides structural insights into an element of cGAS that is amenable to therapeutic exploitation.
Main
In mitosis, when the nuclear envelope disassembles, cGAS is rapidly recruited onto chromosomes and, through this mechanism, is relocated into the nuclear interior16,17 (Fig. 1a and Supplementary Video 1). Recent findings reported that the nuclear pool of cGAS is largely immobile and inactive9. This state is achieved through the tight tethering of cGAS to the acidic patch at the nucleosome surface masking essential elements required for DNA binding and enzyme activation8,10,11,12,13,14. Suppression of intranuclear cGAS is further aided by the chromatin architectural protein BAF, which shields double-stranded DNA from cGAS binding15. These insights elucidated principles of cGAS regulation inside the nucleus. However, how cells coordinate the presence of cGAS on chromatin with general housekeeping genomic processes is unclear.Fig. 1: Identification of SPSB3 and CUL5 in the regulation of nuclear cGAS.
a, Representative image sequence demonstrating cGAS chromosome attachment in mitosis followed by intranuclear redistribution and degradation in cGAS–GFP-expressing HeLa cells (Supplementary Video 1). Scale bars, 10 μm. b, The relative nuclear cGAS–GFP mean fluorescence intensity (MFI) in post-mitotic HeLa cells. n = 29. c, QIBC analysis of endogenous nuclear (left) and cytosolic (right) cGAS levels in HeLa cells. d, The relative nuclear cGAS–GFP MFI in post-mitotic HeLa cells that were treated with epoxomicin (n = 31), bortezomib (n = 30) or DMSO (n = 31). e, Focused RNAi-based screen of UPS factors regulating nuclear cGAS–GFP abundance. Each dot shows the cGAS–GFP mean intensity blotted against integrated intensity. Knockdowns of genes that yielded increased cGAS–GFP levels (>3 s.d.) relative to the control siRNA are shown in yellow. Genes encoding cGAS (dark blue), proteasomal subunits (light blue), CRL5 complex components (dark green) and SPSB3 (light green) are highlighted. f, Schematic of CRL5–SPSB3-directed cGAS ubiquitylation. g, The relative nuclear cGAS–GFP MFI in post-mitotic HeLa cells treated with siRNA against SPSB3 (siSPSB3; n = 18) or CUL5 (n = 14), non-targeting control siRNA (n = 16) or epoxomicin (n = 14). h, QIBC analysis of nuclear cGAS levels in HeLa cells that were treated with siRNA against SPSB3 or CUL5 or control siRNA. i,j, Nuclear (Nuc.) and cytosolic (Cyto.) cGAS–GFP was analysed using immunoblotting in cGAS–GFP-expressing HeLa cells that were treated with siRNA against SPSB3 or control siRNA (i) or MLN4924 (j) and incubated with cycloheximide (CHX) for the indicated time courses. H2B and GAPDH were used as the loading controls. For b, d and g, data are mean ± s.d. Statistical analysis was performed using one-way analysis of variance (ANOVA) with Šídák’s multiple-comparison test (c and h) and two-way ANOVA with Tukey’s multiple-comparison test (d and g). For a, i and j, one representative experiment of three independent experiments is shown.
Xu, P., Liu, Y., Liu, C. et al.
The CRL5–SPSB3 ubiquitin ligase targets nuclear cGAS for degradation.
Nature (2024). https://doi.org/10.1038/s41586-024-07112-w
Copyright: © 2024 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
cGAS is itself attacked by another enzyme, BAF, which breaks it down and inactivates it. However, this in turn needs another layer of complexity to prevent BAF from attacking cGAS at other times, so enter CRL5–SPSB3. This enzyme tags cGAS, marking it for destruction and CRL5–SPSB3 is only normally produced during mitosis.
But, as with any overly complex machine, the more complex it is, the more opportunity there is for something to go wrong, so, because this error-prone Heath-Robinson machine which is there to protect us can sometime treat us as a threat, we have all the autoimmune diseases.
As an example of 'intelligent' design, it is almost as amusingly inept as a Heath-Robinson machine, but as an example of utilitarian evolution by natural selection, is illustrates neatly that no intelligence, no foresight and no ultimate plan was involved and suboptimal solutions which are better than what went before will be retained and become the basis for future development which will often include improving the efficiency of sub-optimal systems or mitigating the effects of failure.
The Unintelligent Designer: Refuting The Intelligent Design Hoax
ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.
Available in Hardcover, Paperback or ebook for Kindle
The Malevolent Designer: Why Nature's God is Not Good
This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.
Illustrated by Catherine Webber-Hounslow.
Available in Hardcover, Paperback or ebook for Kindle
Illustrated by Catherine Webber-Hounslow.
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