sMACs are large macromolecular complexes that are formed during the ageing of the T cells and possibly other cell types too
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.
Pillars of ageing
We have been developing the first in class compounds as detailed below that modulate specific aspects of the immune response by targeting specific points of the complex and the associated telomere transfer reaction.
Disruptors Of sMAC
Target sMAC for ubiquitin dependent proteasome degradation leading to long-term rejuvenation
Negators Of sMAC
Provide reverse agonist activity against an undisclosed sMAC generating pathway leading to life span extension
Lockers Of sMAC
Support an undisclosed molecule (locker) to prevent spontaneous sMAC activation
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