Tag Archives: Autophagy

Decoys and the Strategic Defense Initiative (SDI)

It will take a detour through history to understand how lung cells try to defeat MRSA (Methicillin Resistant Staph. Aureus), a very nasty bug.

Back in 1983 President Reagan proposed building an antiMissile defense system, which would shoot down Russian InterContinental Ballistic Missiles (ICBMs) aimed at us.  Almost every scientist of note said it was impossible technically, because even if you could shoot down one (which they didn’t think you could), the Russians would send multiple decoy ICBMs without warheads.  It was an enormously expensive project and one the Russians had no hope of matching.  People still argue whether their attempt to match the US caused the Russians  to collapse — https://history.howstuffworks.com/history-vs-myth/who-won-cold-war1.htm — although collapse they did being overextended in Afghanistan (as we’ve been for 20 years).

But that’s exactly what A549 cells (derived from lung epithelium) do to fake out MRSA according to Nature vol. 579 pp. 260 – 264 ’20.  One of the reasons MRSA is so nasty is that it secretes a protein (alpha toxin) which forms holes in cells it binds to.  Well alpha toxin has a target it must bind to cause trouble, otherwise it would form holes in everything including itself.  The target is an enzyme on the surface of the cell called ADAM10, which is a protease found on the cell membrane.

You may not have thought of it, but when you diet, your cells eat themselves, rather than just sloughing of the cells in the fat you don’t like (love handles, double chin etc. etc.).  Wouldn’t that be nice though.  The process is called autophagy, in which membranes appear, surround small bits of each cell and them fuse with the lysosome, which breaks the contents down into metabolically useful material (sugars, fats, amino acids).  Some 41 different proteins are involved called ATG’s (for AuTophagy Gene).

But the autophagy genes can also be used to secrete stuff to the outside of the cell, and in fact that’s how the lung cells beat MRSA, they secrete zillions of little vesicles called exosomes (an entirely interesting newly discovered story, to be covered at another time), containing the target of alpha toxin — ADAM10.  Clever no?  The authors were so excited they invented a new word for it the defensosome. The ATG involved is called ATG16L1.  Previously the function of ATG16L1 appeared well defined, conjugating phosphatidylethanolamine to LC3, a ubiquitinLike molecule to form the autophagosome.  That’s probably nomenclature overload, but it’s worthwhile getting an appreciation of the complicated things going on inside our cells.

 

A sad (but brilliant) paper about autophagy

Over the past several decades I’ve accumulated a lot of notes on autophagy (> 125,000 characters).  It’s obviously important, but in a given cell or disease (cancer, neurodegeneration) whether it helps a cell die gracefully or is an executioner is far from clear.  Ditto for whether enhancing or inhibiting it in a given situation would be helpful (or hurtful).

A major reason for the lack of clarity despite all the work that’s been done can be found in the following excellent paper [ Cell vol. 177 pp.1682 – 1699 ’19 ].  Some 41 proteins are involved in autophagy in yeast and more in man.  Many are described as ATGnn (AuTophagy Gene nn).

Autophagy is a complicated business: forming a membrane, then engulfing various things, then forming a vacuole,  then fusing with the lysosome so that the engulfees are destroyed.

The problem with previous work is that if a protein was found to be important in autophagy, it was assumed to have that function and that function only.   The paper shows that core autophagy proteins are involved in (at least) 5 other processes (endocytosis, melanocyte formation, cytokinesis, LC3 assisted phagocytosis and translocation of vesicles from the Golgi to the endoplasmic reticulum).

Experiments deleting or  increasing a given ATGnn were assumed to produce their biological effects by affecting autophagy.

The names are unimportant.  Here is a diagram of 6 autophagy proteins forming a complex producing autophagy

1 2 3

4 5 6

So 2 binds to 1, 3 and 5

But in endocytosis

1 2 3

5

form an important complex

In cytokinesis the complex formed by

2 3

5

is important.

Well you get the idea.  Knocking out 2 has cellular effects on far more than autophagy.  So a lot of work has to be re-thought and probably repeated.

Notice that all 6 functions involve movement of membranes.  So just regard the 6 proteins as gears of different diameters which can form the guts of different machines as they combine with each other (and proteins specific to the other 5 processes mentioned) to move things around in the cell.

It’s probably too good to be true

SR9009 and SR9011 are drugs which selectively kill cancer cells by an entirely new mechanism.  They mess with DNA but don’t mutate it.  http://www.nature.com/articles/nature25170 [ Nature vol. 553 pp. 351 – 355 ’18 ] has the details.

First a bit of background.  How do the classic hormones (estrogen, androgen, thyroid, adrenal steroids) do what they do?  Clearly they change the expression of many many genes as any post-pubertal woman will attest.  They bind to proteins called nuclear hormone receptors, changing their shape so they can bind to DNA and change gene expression.   We have 48 of them in our genome.  For a long time we didn’t know what the natural ligands of many actually were.  These were called orphan nuclear hormone receptors.  I’m not sure how many orphans are left.

 

SR9009 and SR9011 bind to REV-ERBalpha and REV-ERBbeta which are nuclear hormone receptors. They are agonists (e.g. they cause SR9009 and 11 to do what they do)  Their natural ligand is heme (which isn’t a hormone) and they are involved in the circadian clock.   However they also act as repressors of processes involved in tumorigenesis, including metabolism, proliferation and inflammation.

So the authors threw the agonists at a variety of tumor cells (brain cancer, leukaemia, breast cancer, colon cancer and melanoma) and watched them commit suicide (apoptosis).  They had no effect on normal cells !

How do they work?  There is only speculation at this point.  It is known that SR90xx’s inhibit autophagy, something cancer cells depend on for nourishment.  Normal cells only use autophagy under starvation conditions. They also repress several lipogenic enzymes (fatty acid synthase etc. etc) and cancer cells are said to be dependent on de novo lipogenesis (if they want to proliferate, they got to make a lot of membrane).

It’s almost too good to be true.  Stay tuned.