Proteolethargy is a pathogenic mechanism in chronic disease, 2024, Dall’Agnese et al

Proteolethargy is a pathogenic mechanism in chronic disease
Alessandra Dall’Agnese; Ming M. Zheng; Shannon Moreno; Jesse M. Platt; An T. Hoang; Deepti Kannan; Giuseppe Dall’Agnese; Kalon J. Overholt; Ido Sagi; Nancy M. Hannett; Hailey Erb; Olivia Corradin; Arup K. Chakraborty; Tong Ihn Lee; Richard A. Young

SUMMARY
The pathogenic mechanisms of many diseases are well understood at the molecular level, but there are prevalent syndromes associated with pathogenic signaling, such as diabetes and chronic inflammation, where our understanding is more limited. Here, we report that pathogenic signaling suppresses the mobility of a spectrum of proteins that play essential roles in cellular functions known to be dysregulated in these chronic diseases. The reduced protein mobility, which we call proteolethargy, was linked to cysteine residues in the affected proteins and signaling-related increases in excess reactive oxygen species. Diverse pathogenic stimuli, including hyperglycemia, dyslipidemia, and inflammation, produce similar reduced protein mobility phenotypes. We propose that proteolethargy is an overlooked cellular mechanism that may account for various pathogenic features of diverse chronic diseases.

HIGHLIGHTS
• Pathogenic signaling leads to reduced mobility of proteins with diverse functions

• Reduced protein mobility (proteolethargy) is linked to dysregulated redox environments

• Diverse pathogenic stimuli associated with chronic diseases cause proteolethargy

• Proteolethargy may account for diverse cellular phenotypes seen in chronic diseases

Link | PDF (Cell) [Paywall]

 

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I wonder if we'll detect any potentially relevant gain of cysteine mutations in DecodeME.

 

Barely understand, but if the main idea, proteolethargy, is that a large variety of proteins are literally swimming more slowly through the blood, then maybe the body would upregulate all those proteins since it's taking them longer than normal to get to their destination - it would compensate by making more?

One of the PolyBio talks was about widespread protein upregulation in long COVID.

 

I didn't think the paper was suggesting mutations in cysteine coding by DNA?
I cannot yet see quite what they are suggesting but I assume some form of post-translational cysteine modification of disulphide bonds.

 

Movement of proteins in blood is 99% due to the heart pumping. I think they are talking about movement of proteins from one side of a cell to another - i.e. inside a cell. That is presumably due to some change in surface residues like cysteine.

 

Oh understood, but might upregulation of these proteins still be a consequence in that case?

 

I don't see any particular reason why. I am finding it hard to see how this concept of proteolethargy relates to disease if it occurs in both diabetes and inflammation, which present with unrelated symptoms. Much of the time diabetics with functional insulin lack are asymptomatic until complications set in or high sugar produces diuresis.

 

I think they are suggesting that the subset of normal proteins that have exposed cysteine may be subject to this pathophysiology, but that other proteins might also be involved in some individuals when they have mutations that produce an otherwise unremarkable change to a cysteine residue. I can see that potentially this could explain a genetic predisposition toward ME/CFS. An example might be if GRP78 could be impaired in its translocation between ER lumen, cell surface and nucleus in response to ER stress. Perhaps then regulation of WASF3 might be affected, which then tends to accumulate and interfere with complex III/IV assembly (per Huang et al).

They then showed that the proteins that don't have the surface-exposed cysteine residue were not directly subject to intracytoplasmic slowing, although there was a small secondary effect on them.

I think they're suggesting that oxidative stress would have an effect on proteins in specific cells (likely more than one cell type) contributing to specific diseases, rather than necessarily the whole explanation. I don't know if it would be all or nothing in terms of which proteins, but it sounds as if potentially it could be all that have the surface cysteine / risk of forming disulfide bonds.

So simplistically ME/CFS might become a stable pathological state if there were initiation with high ROS during infection and then continued reinforcement with mitochondrial dysfunction that keeps the ROS generation high enough?? What then stops that happening in everyone? Double-hit? Some threshold of high-enough ROS generation? (Noting that identical twins can be affected / unaffected)

 

ROS generation in infection is local and as far as I know not a major feature of viral infection.
As an immunologist this quotes all sound to me like stringing together various popular memes without any real understanding of inflammation.

And presumably if people had mutations in gremlin encoding unusual cysteines that led to movement problems that would not need to have anything to do with ROS anyway.

To me it is a bit like trying to explain why someone won a game of bridge using the rules of snap. Nothing is in perspective.

 

This is an unusual but deeply-researched paper, by leading biologists out of MIT in the US. Their work is beautifully explained by @SNT_gatchaman .

If I understand it right they're proposing a whole new hypothesis for why oxidative stress can impair cellular function: simply by slowing the rate at which reactions happen (fewer collisions) and the speed with which proteins move to their destinations.

Their conclusion is consistent with their findings but of course it might not pan out. A new paradigm like this needs to be solidified.

If it is supported, measuring protein speeds could become useful to see how well a proposed treatment is working, in vitro. Have an in vitro model, apply some molecule, see if the proteins that trail a cysteine speed up at all. It's not obvious you could measure it in vivo.

I know I clicked on it because the term proteolethargy is novel and fun, it's not upstream enough to be specific to me/cfs, and the authors don't claim it is. But it certainly could be a downstream factor that is in play, especially in PEM. Oxidative stress is famously one of our problems. And some people claim benefit from NAC.