A Longevity protease

Network Image

This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.

Zinc metalloproteinase ZMPSTE24 (FACE1, STE24 yeast a-factor maturation) is a member of the peptidase M48A family that proteolytically removes the C-terminal residues of farnesylated proteins. This multi-pass membrane protein acts on lamin A/C (green node), intermediate filament proteins and the major structural proteins of the nuclear lamina, a filamentous meshwork beneath the inner nuclear membrane. Defects in ZMPSTE24 cause mandibuloacral dysplasia with type B lipodystrophy (MADB) [MIM:608612]. Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of the cranial suture, joint contractures, and types A or B patterns of lipodystrophy. Type B lipodystrophy observed in MADB, is characterized by generalized fat loss. Defects in ZMPSTE24 also cause lethal tight skin contracture syndrome [MIM:275210] or restrictive dermopathy (RD), a rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, distinct facial features (i.e., small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Live-born children usually die within the first week of life.

Multiple studies have shown that proteolytic activities decrease with age, a situation that leads to the accumulation of damaged macromolecules during physiological aging. Contrary to this well-established concept, it was recently proposed that the nuclear architecture defects occurring in ZMPSTE24-/- progeroid (premature aging) mice activate an anti-aging response first characterized by transcriptional alterations in metabolism regulatory genes and profound changes in circulating blood glucose and hormone levels. These changes likely lead to activation of the LKB1-AMPK pathway and subsequent inhibition of mTOR (node in orange), which in turn causes autophagy, an essential component of pro-survival pathways in eukaryotes.

It will be very interesting to explore the possibility that a metabolic checkpoint similar to what is observed in ZMPSTE24-/- mice could operate in patients affected by devastating human progeroid syndromes such as Hutchinson-Gilford disease, which are also caused by defects in nuclear lamina architecture. The recent observation that nuclear envelope abnormalities could be a central cause of aging raises the possibility that normal physiological aging and/or senescence involve the chronic activation of autophagy, an originally intended pro-survival strategy that may turn out to be a pro-aging mechanism.

Below are links to NCBI by PMID supporting this network.

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7654502 7709742 7728088 7848622 7881656 7999889 8230615 8363904 8366013 8378773
8378774 8435794 8443001 8470519 8587406 8612261 8639527 8671782 8796515 8923140
8950579 9014358 9015945 19020898