Tag Archives: lps

Solid evidence for acupuncture at last

The early hype about acupuncture was so extreme (bathwater) that I stopped looking for the medical baby within.  Part of the hype was a reaction against all things western.

However when stimulation of a mouse at the knee point (ST36) decreases mortality due to exposure to lipopolysaccharide by 40%, it’s time to sit up and take notice [ Nature vol. 598 pp. 573 – 574, 641 – 645 ’21 ].

Not only that but the authors found the neurons responsible for the effect.  These neurons in the dorsal root ganglion express the G Protein Coupled Receptor (Prokr2) which is a  receptor for prokineticin, a secreted protein which increases gut motility.

Stimulation of these neurons (or the point behind the knee they innervate) produces anti-inflammatory effects.  Destruction of these neurons (by expressing diphtheria toxin in them) prevents low intensity stimulation of ST36 from dampening inflammation.

The paper even gives a possible explanation for some of the irreproducible results in the field.  High intensity of stimulation of ST36 activates the sympathetic system, while low intensity stimulation activates the parasympathetic nervous system.  The latter activates the vagus nerve which stimulates the adrenal medulla to produce catecholamines (which are anti-inflammatory).  So high intensity stimulation of the same site produces no useful therapeutic effect.

I never thought I’d see high quality work like this on acupuncture, but there it is.  More is sure to follow.

Ubiquitination isn’t just for proteins

Time to look up from the plow biochemists.  Everyone knows that ubiquitin is added to proteins to destroy them.  The carboxy terminal amino acid of ubiquitin (glycine) forms an amide with the epsilon amino acid of a lysine called an isopeptide bond, and off  the protein goes to the proteasome for destruction.  This is simplistic and ubiquitination has many other other roles in the cell, but there isn’t time for it here.

I couldn’t resist putting in two interesting facts about ubiquitin.

#1. Like sharks,  evolution hasn’t changed ubiquitin much — only 3/71 amino acids differ between yeast and us.

#2 Ubiquitin is so stable that boiling water doesn’t denature it < Science vol. 365 pp. 502 – 505 ’19 >.

We have over 600 E3 enzymes (ubiquitin ligases), 40 E2 enzymes, and 8 E1 enzymes, and all 3 types are required to add ubiquitin to proteins.

Once a bacterium gets inside a cell, one of the ways the innate immune system attacks it is by ubiquitinating its proteins.  Nothing out of the ordinary there.

Salmonella (the organism responsible for most cases of food poisoning) is one such.  Our cells ubiquitinate the hell out of it.  However Nature vol. 594 pp. 28 – 29, 111 – 116 ’21 shows that, not just Salmonella proteins are the only sites of ubiquitination.  We also ubiquitinate endotoxin (lipopolysaccharide) which is a combination of sugars and lipids, with nary an amino acid in sight.  Endotoxin is a component of the outer membrane of every Gram negative bacterium, so the effect is likely not confined to Salmonella.

Even more spectacular is the enzyme adding ubiquitin.  It is called RNF213 (aka Mysterin), which looks like nothing the classic E3 enzymes we know and love.  For one thing in addition to E3 activity, it has a motor domain, a zinc binding domain and other domains of unknown function.  It’s a real monster with 5,184 amino acids and a molecular mass of 584 kiloDaltons.

There is a lot of interesting molecular biology to RNF213 — mutations cause Moya moya disease.

But the papers are particularly interesting because they show a lot of work of a new type needs to be done.

What else does Mysterin ubiquitinate?  Are there other enzymes in the cell adding ubiquitin, and if so, what do they ubiquitinate?

Definitely time to expand the well plowed field of ubiquitin.