Platform

sMACs are large macromolecular complexes that are formed during the ageing of the T cells and possibly other cell types too. They consist of a set of cellular rheostats (sestrins), an energy sensor (the heterotrimer alpha, beta, gamma kinase AMPK), and three effector kinases (the mitogen activated protein kinases (MAPK): JNK, ERK and p38). While these three essential class of components have been identified, molecular analysis suggests that about 50% of the complex is yet to be defined. We have therefore been working to further dissect the biochemical basis of sMAC function and have now identified new undisclosed targets that regulate genesis of the complex as well the site specific MAPK activation upon binding of sestrins to the complex.

Upon binding of sestrins to the complex, in fact, ATP is unleashed from AMPK leading to its kinase activation that subsequently causes induction of global MAPK signaling cascades initiated by effector kinase auto-phosphorylation. This activated complex is present mostly in the senescent T cells, or their progenitors (that form, for instance, upon a failed round of telomere transfer), leading to deterioration of the immune protective response, with consequent onset of infections, cancers and, eventually, death. Despite this, activation of the complex may still be beneficial in situations where overt immune activation leads to auto-reactive, self damaging responses such as auto-immune disorders.