So I'm leafing through my good old weekly Science, as ever, and looky here, what do I find...the fantastic duo Mukhopadhyay and Riezman at it again. In the 12 January 2007 issue -- yes, the issue with the "scanning electron micrograph of Trichomonas vaginalis parasites (gray-green) adhering to vaginal epithelial cells (pink)" that look like strawberries, on the cover -- and they've got a research review piece, "Proteasome-Independent Functions of Ubiquitin in Endocytosis and Signaling," and I admit there were some parts I simply didn't quite follow. They start with the obvious: "Ubiquitination is a reversible posttranslational modification of cellular proteins." That's not the problem. My 5-year-old knows that. We run ubiquitination drills almost every night. (His idea.) What cranks me up is the stuff on p. 204, top left column.
There, the cheeky Debdyuti and Howard wax poetic on Ubiquitination having "come to light as a major regulator of the nuclear factor (NF) kB signaling pathway." And get this:
NF-B transcription factors are activated by the proinflammatory cytokines [tumor necrosis factor- (TNF-) and interleukin-1Ã (IL-1Ã)], resulting in degradation of an inhibitor of NF-B (IB), which binds to NF-B and retains it in the cytoplasm (Fig. 2). IB is phosphorylated by a kinase [IB kinase (IKK)], which has a regulatory subunit called NF-B essential modulator (NEMO). NEMO is modified by UbK63 polyubiquitination by the TNF- receptor-associated factor 6 (TRAF6) (44). UbK63 on NEMO activates IKK, which phosphorylates IB, targeting it for polyubiquitination and proteasomal degradation (45). This action liberates NF-B. Another kinase that activates IKK is TGF-Ã-activated kinase (TAK1). TAK1-binding proteins (TAB1, TAB2, and TAB3) bind to TRAF6 and TAK1, stimulating its kinase activity, and preferentially bind UbK63 (46). Furthermore, the TRAF6-TAB2-TAK1 complex interacts with IKK. So, UbK63 may function as part of a scaffold to assemble a TAK1-IKK-containing signaling complex (47). When NF-B activation is induced by TNF-, receptor-interacting protein (RIP), which is important for receptor complex assembly, undergoes UbK63 polyubiquitination. NEMO binds to UbK63-polyubiquitinated RIP and thereby recruits IKK to the TNF receptor. This recruitment could explain the propagation of signal from the activated TNF receptor to the activation of IKK and NF-B. NEMO also stabilizes RIP through interaction with its UbK63 chains, and thus the binding of NEMO could impair RIP interaction with another protein, A20 (48). A20 inhibits NF-B signaling by sequentially removing UbK63 chains from RIP and targeting it for degradation through ligation of UbK48 chains (6).
I mean, I mean, please! Yes, "UbK63 may function as part of a scaffold to assemble a TAK1-IKK-containing signaling complex," but tell me, how, just how, does this "explain the propagation of signal from the activated TNF receptor to the activation of IKK and NF-B"?
Anyone? Anyone?
It is totally beyond me.
And like this figure below helps?
They call this "Fig. 2. Activated IL-1 receptor (IL-1R) stimulates TRAF6-dependent UbK63 polyubiquitination of IKK (NEMO)." But I don't even know what to believe anymore.
Maybe Dave knows.
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This is either the funniest, snarkiest, take on science writing I've ever read; or, perhaps the most jargon-heavy, inside-joke I've ever read.
The great thing is, I like it as either. In grad school I hung out in a ubiquitination lab down in Florida, it's been too long since I've thought about it.
Clearly, Al Gore needs to make a movie out of this.
Things have gone too far once the word "signalosome" gets thrown around.
Heh. After having read about 26273961276 papers on ubiquitinations (give or take a few) I actually do understand, but I'll admit it's not a great read. This is what all ubiquitination-as-sorting-signal papers look like, though.
Summary of the field of ubiquitination:
1. Add a tail of ubiquitin molecules to a protein (polyubiquitination) and it gets degraded (it's really gone now!)
2. Add one or more single ubiquitin molecules to a protein, and it moves to another compartment in the cell (it's not really gone, but it's in another place and not accessible right away)
3. Write paper with as many acronyms as possible.
(Parenthetically speaking: Eva, I'm gratified to see your comment, and to know that at least someone follows this. And fear not, Robert P., you're way ahead of me in terms of ubiquitin talk, I assure you. Ben)
Duh, wha-?
This may be a bit late, but comment #4 actually helped me organise my laymans terms presentation due next week.
If you still exist Eva, thanks :)
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