Cytoplasmic stress granules: a cause of cellular dysfunction in ME/CFS?

These stress granule thingies have been following me like a bad smell these last few months. First they popped up as a side remark in one podcast, then in another. And now again in Philip Ball's book How Life Works: A User's Guide to the New Biology*. So third time round I thought I'd better look them up. I mean, given how often cellular stress response hypotheses crop up in the ME field it's rather surprising such a wonderful term as stress granules has somehow gone under the radar

A very brief internet search for stress granules and ME/CFS came up with precisely zilch.

A search on S4ME came up with two threads, neither of them about ME.

• https://www.s4me.info/threads/ras-gtpase-activating-protein-binding-protein-1-g3bp1.33133/
• https://www.s4me.info/threads/molec...s-condensates-2023-xiaojie-zhang-et-al.33129/

But here's a recent general review on the things:

Pathophysiology of stress granules: An emerging link to diseases,, 2022, Wang J et al
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8846937/

And another, more extensive review:

Targeting stress granules: A novel therapeutic strategy for human diseases, 2020, Wang F et al
www.ncbi.nlm.nih.gov/pmc/articles/PMC7428673/

I've only skimmed the reviews. There seem to be quite a few different types of stress granules - some better understood than others - with different condensation-dissolution dynamics, made up of different molecules, and relevant to very different diseases. So stress granules appears to be quite a broad term. Maybe that's reason they haven't been mentioned (much?) in the ME field? Maybe some studies have in fact investigated parts of particular stress granules without using the term itself?

According to the reviews they've been looked at in acute corona virus infections (not Long Covid I don't think) but I haven't looked into this

*Anyone happen to have the supplementary material with all the illustrations? My Kobo audiobook subscription service still hasn't figured out how to provide those. Rarely a major issue but for a technical book like this one the illustrations would be seriously helpful to have
I've got my sticky fingers on these now and they're proving very helpful. The book itself does a great job of giving my semi-fossilised biology knowledge a mighty good shake up. If anyone else is interested I recommend going for a text edition if reading is no problem. If like me you need audio make sure you get it from a supplier who can supply the supplementary material (i.e. not Kobo, they've been spectacularly unhelpful)

 

I was imagining some sort of lumps under the skin in response to stress.

 

Generative AI thinks they look like this.

 

I wondered what flavour gravy they would make - probably down to being dragged up in the North East of England in the 70s/80s.

 

My half crown's on kali.

 

There is always talk of heat shock proteins when people don't know.
And oxidative stress.
And granules.

And every time it is a totally new way of looking at whatever it was we were looking at.

I suspect the granules taste of star anise.
All except the orange ones, that is.

 

that'll be the OXOdative stress response

 

Either that or Barbecue Spice Rub

 

Stress granules are confusing. The only thing I know for sure is they need a rebrand, ought to be named something latinate and technical to get respect!

 

Not quite how I expected this thread to go

Maybe a moderator could change the title - I can't seem to do this - to indicate this isn't about ear seeds or some other such nonsense, maybe add something like (actual cellular biology term) after stress granules

But yes, stress granules is a weird term. My first mental association was fertiliser granules dissolving inside a cell which would be rather counterproductive, who needs cellular stress to grow!

In the event it looks like at least some types of stress granules do the opposite, one could argue they help de-stress the cell - and that without any CBT Cellular Behabioural Therapy - though it's a double-edged sword, things going wrong with stress granules can have nasty consequences

 

Apart from the papers initially linked by Ravn, here are some other recent review articles —

Principles and Properties of Stress Granules (2016)

Stress granules are assemblies of untranslating messenger ribonucleoproteins (mRNPs) that form from mRNAs stalled in translation initiation. Stress granules form through interactions between mRNA-binding proteins that link together populations of mRNPs. Interactions promoting stress granule formation include conventional protein–protein interactions as well as interactions involving intrinsically disordered regions (IDRs) of proteins.

Assembly and disassembly of stress granules are modulated by various post-translational modifications as well as numerous ATP-dependent RNP or protein remodeling complexes, illustrating that stress granules represent an active liquid wherein energy input maintains their dynamic state. Stress granule formation modulates the stress response, viral infection, and signaling pathways. Persistent or aberrant stress granule formation contributes to neurodegenerative disease and some cancers.

Link | PDF (Trends in Cell Biology)

Molecular mechanisms of stress granule assembly and disassembly (2021)

Stress granules (SGs) are membrane-less ribonucleoprotein (RNP)-based cellular compartments that form in the cytoplasm of a cell upon exposure to various environmental stressors. SGs contain a large set of proteins, as well as mRNAs that have been stalled in translation as a result of stress-induced polysome disassembly. Despite the fact that SGs have been extensively studied for many years, their function is still not clear. They presumably help the cell to cope with the encountered stress, and facilitate the recovery process after stress removal upon which SGs disassemble. Aberrant formation of SGs and impaired SG disassembly majorly contribute to various pathological phenomena in cancer, viral infections, and neurodegeneration.

The assembly of SGs is largely driven by liquid-liquid phase separation (LLPS), however, the molecular mechanisms behind that are not fully understood. Recent studies have proposed a novel mechanism for SG formation that involves the interplay of a large interaction network of mRNAs and proteins. Here, we review this novel concept of SG assembly, and discuss the current insights into SG disassembly.

Link | PDF (Biochimica et Biophysica Acta (BBA) - Molecular Cell Research)

The Integral Role of RNA in Stress Granule Formation and Function (2021)

Stress granules (SGs) are phase-separated, membraneless, cytoplasmic ribonucleoprotein (RNP) assemblies whose primary function is to promote cell survival by condensing translationally stalled mRNAs, ribosomal components, translation initiation factors, and RNA-binding proteins (RBPs). While the protein composition and the function of proteins in the compartmentalization and the dynamics of assembly and disassembly of SGs has been a matter of study for several years, the role of RNA in these structures had remained largely unknown. RNA species are, however, not passive members of RNA granules in that RNA by itself can form homo and heterotypic interactions with other RNA molecules leading to phase separation and nucleation of RNA granules. RNA can also function as molecular scaffolds recruiting multivalent RBPs and their interactors to form higher-order structures.

With the development of SG purification techniques coupled to RNA-seq, the transcriptomic landscape of SGs is becoming increasingly understood, revealing the enormous potential of RNA to guide the assembly and disassembly of these transient organelles. SGs are not only formed under acute stress conditions but also in response to different diseases such as viral infections, cancer, and neurodegeneration. Importantly, these granules are increasingly being recognized as potential precursors of pathological aggregates in neurodegenerative diseases.

In this review, we examine the current evidence in support of RNA playing a significant role in the formation of SGs and explore the concept of SGs as therapeutic targets.

Link | PDF (Frontiers in Cell and Developmental Biology) [Open Access]

Stress granules, RNA-binding proteins and polyglutamine diseases: too much aggregation? (2021)

Stress granules (SGs) are membraneless cell compartments formed in response to different stress stimuli, wherein translation factors, mRNAs, RNA-binding proteins (RBPs) and other proteins coalesce together. SGs assembly is crucial for cell survival, since SGs are implicated in the regulation of translation, mRNA storage and stabilization and cell signalling, during stress. One defining feature of SGs is their dynamism, as they are quickly assembled upon stress and then rapidly dispersed after the stress source is no longer present.

Recently, SGs dynamics, their components and their functions have begun to be studied in the context of human diseases. Interestingly, the regulated protein self-assembly that mediates SG formation contrasts with the pathological protein aggregation that is a feature of several neurodegenerative diseases. In particular, aberrant protein coalescence is a key feature of polyglutamine (PolyQ) diseases, a group of nine disorders that are caused by an abnormal expansion of PolyQ tract-bearing proteins, which increases the propensity of those proteins to aggregate. Available data concerning the abnormal properties of the mutant PolyQ disease-causing proteins and their involvement in stress response dysregulation strongly suggests an important role for SGs in the pathogenesis of PolyQ disorders.

This review aims at discussing the evidence supporting the existence of a link between SGs functionality and PolyQ disorders, by focusing on the biology of SGs and on the way it can be altered in a PolyQ disease context.

Link | PDF (Nature Cell Death & Disease) [Open Access]

Stress granules: functions and mechanisms in cancer (2023)

Stress granules (SGs) are non-enveloped structures formed primarily via protein and RNA aggregation under various stress conditions, including hypoxia and viral infection, as well as oxidative, osmotic, and heat-shock stress. SGs assembly is a highly conserved cellular strategy to reduce stress-related damage and promote cell survival. At present, the composition and dynamics of SGs are well understood; however, data on the functions and related mechanisms of SGs are limited. In recent years, SGs have continued to attract attention as emerging players in cancer research. Intriguingly, SGs regulate the biological behavior of tumors by participating in various tumor-associated signaling pathways, including cell proliferation, apoptosis, invasion and metastasis, chemotherapy resistance, radiotherapy resistance, and immune escape. This review discusses the roles and mechanisms of SGs in tumors and suggests novel directions for cancer treatment.

Link | PDF (Cell & Bioscience) [Open Access]

Regulation of stress granule formation in human oligodendrocytes (2024)

Oligodendrocyte (OL) injury and subsequent loss is a pathologic hallmark of multiple sclerosis (MS). Stress granules (SGs) are membrane-less organelles containing mRNAs stalled in translation and considered as participants of the cellular response to stress.

Here we show SGs in OLs in active and inactive areas of MS lesions as well as in normal-appearing white matter. In cultures of primary human adult brain derived OLs, metabolic stress conditions induce transient SG formation in these cells. Combining pro-inflammatory cytokines, which alone do not induce SG formation, with metabolic stress results in persistence of SGs. Unlike sodium arsenite, metabolic stress induced SG formation is not blocked by the integrated stress response inhibitor. Glycolytic inhibition also induces persistent SGs indicating the dependence of SG formation and disassembly on the energetic glycolytic properties of human OLs.

We conclude that SG persistence in OLs in MS reflects their response to a combination of metabolic stress and pro-inflammatory conditions.

Link | PDF (Nature Communications) [Open Access]

 

Well that seems to prove it.
Anything trendy and irrelevant will have masses of review articles!!

If a biological concept that gets a name like this it means it is being worked on by people who do not really understand how to do biology. Maybe someone has found some heaps of RNA, which might be interesting. But they should be called bits of RNA. After a lifetime in the field I am afraid I have no respect for 'actual cellular biological terms' otherwise.

 

Yes, I've never heard of them until Ravn's post. I agree they could have gone with a better name! I just skimmed the abstracts but thought worth posting a few accessible links in case of interest.

 

It sounds like there's potential for these protein bits to play an important role in proper biological functions, but it sounds like the knowledge is at the stage of when chemical theory was first announced. Great potential for understanding how the world works, and potential for intentionally reacting chemicals to do useful things, but lots needed to be learned first. Until they can do real-time analysis of these protein bits in-situ, blaming any diseases on them is like blaming gremlins.

 

As with the Baader-Meinhof phenomenon, they came up in a preprint yesterday SARS-CoV-2 Nsp15 antagonizes the cGAS-STING-mediated antiviral innate immune responses (2024, Preprint: BioRxiv)

 

Ah, but 'stress granules' is so much more memorable than 'liquid-liquid phase separation condensates' (and if you're hoping people will stop following fads and fashions and jumping on band wagons, I've bad news for you...)

Ok, so the following thought experiment is firmly in 99.99% likely to be a dumb idea territory, buildt on ignorance, but here goes anyway, on the off-chance it may spark some better ideas

My understanding of SG is based on skimming about 1/3 of 2 reviews, it could be totally off track, but let's assume this simplistic summary is in the ball park:

• SGs form when a cell is under stress
• certain molecules (e.g. RNAs) condense together so they don't interfere with the cell's stress response
• once the acute stress is over the SGs dissolve again

If SGs fail to resolve correctly they can become a sticky mess and this could contribute to neurodegenerative diseases (which ME isn't, most probably). One could say this part of the cellular stress response is stuck on 'on'. While there's been a lot of talk about a stuck stress response in ME, could the problem be not that it's stuck on 'on' but rather that it's stuck on 'off', at least for the SG part of the stress response?

If SGs fail to form correctly, could it be that some of the molecules normally sequestered inside them now float around the cell causing trouble and somehow alerting the wider immune system? I'm thinking here of the sort of minor stressors like from exercise that a cell would normally deal with by itself without calling for a full scale immune response

In this scenario there might not be any measurable difference in the amount of the various molecules, there's the same amount, they're just distributed wrongly

If true, this would raise two big questions

1. why don't the SGs form normally? [see @SNT Gatchaman's post above for one possible answer]
   
2. what particular molecules cause what sort of trouble how, when not contained in SGs?