Chaperone-mediated autophagy

Nature Medicine is not one of the journals I usually follow. Today, several of my literature alerting services – and several press releases as well – pointed to a paper in the AOP section of Nature medicine that appeared to be a must-read. As usual, the press releases are vague about what the study actually does, but they contain all the words needed to get me interested: autophagy, ubiquitin-proteasome system, Alzheimer’s and Parkinson’s disease – and, of course, the ultimate cure for aging. If you are a liver, that is. The paper by Cong Zhang and Ana Maria Cuervo is entitled Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function, which in the press coverage becomes Cellular rubbish may hold key to ageing process or Big step in the fight against aging or In scientific first, Einstein researchers correct decline in organ function associated with old age.

Despite these gross exaggerations, I do not regret having read the paper, as it has introduced me to a potentially interesting concept called ‘chaperone-mediated autophagy’ (CMA). Judging by the name, this is something I should have known about before – I must admit that this is not the case. One of the reasons is that there appears to be only one group (and their offshoots) working on CMA, They seem to have discovered it, too. If you want to know the details, have a look at this open-access review by J. Fred Dice.

In brief, CMA is a weird way of degrading cytoplasmic proteins. No, not by the proteasome, by the lysosome! After reading the CMA review, there is one thing for sure: had it been my task to intelligently design nature, CMA is not a route I would have taken into consideration. Ok, maybe after a few bottles of a good Chianti. But then, there is ERAD, where lumenal proteins are squeezed back into the cytoplasm by some obscure mechanism, with the idea to degrade them by the proteasome. Why not use a similarly obscure mechanism to squeeze cytoplasmic proteins into the lysosomal lumen for degradation? Apparently, selected cytoplasmic proteins that harbour a certain motif (the KFERQ-related peptide) are recognized by cytoplasmic Hsc70 chaperones together with their usual set of co-chaperones (Hip, Hsp40, Hsp90, Bag-1). Next, this substrate/chaperone assembly is recognized by a receptor consisting of the lysosome-associated membrane protein LAMP-2a, a splice form of the LAMP2 gene. LAMP2 forms a multimeric complex in the lysosomal membrane, which is thought to act as the translocation pore. Apparently, lysosomal chaperones are also required for pulling the unfolded protein through the pore.

This intriguing mechanism has a fundamental flaw, though: it does not involve ubiquitin. As everybody knows, ubiquitin is required for every interesting biological process. Thus, there is clearly some more work to do. It would also help, if a completely unrelated group would contribute to the CMA field. As I have talked about before, I am always skeptic about new proteins/genes/pathways/processes that have only been observed by a single group.

What is the connection between CMA and aging? It had been previously observed (by the Cuervo group) that CMA is abolished if LAMP-2a is knocked down, and that both CMA and lysosomal LAMP-2a levels decline with age. In the new Nature Medicine paper, Zhang and Cuervo have generated a mouse model where the expression level of LAMP-2a in the liver can be modulated. When analyzing aged mice with a continuously high LAMP-2a expression in the liver, the authors found that CMA efficiency did not decline with age and that  the aged liver contained much less intracellular accumulation of damaged proteins. Also, liver function of aged mice with high LAMP-2a level was comparable to that of young mice and better than that of untreated mice at the same age. No matter what you think about CMA, this is a very interesting result.

Update: After doing some more searches, I noticed that there is much more literature on CMA than I previously thought, with different groups involved as well. The “KFERQ” motif has even been reviewed in TiBS as early as 1990. I really wonder how this could have eluded me.