INSR
Insulin receptor precursor (EC 2.7.10.1) (IR) (CD220 antigen) [Contains: Insulin receptor subunit alpha; Insulin receptor subunit beta]
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Mammalian species differ up to 100-fold in their aging rates and maximum lifespans. Long-lived mammals appear to possess traits that extend lifespan and healthspan. Genomic analyses have not revealed a single pro-longevity function that would account for all longevity effects. In contrast, it appears that pro-longevity mechanisms may be complex traits afforded by connections between metabolism and protein functions that are impossible to predict by genomic approaches alone. Thus, metabolomics and proteomics studies will be required to understand the mechanisms of longevity. Several examples are reviewed that demonstrate the naked mole rat (NMR) shows unique proteomic signatures that contribute to longevity by overcoming several hallmarks of aging. SIRT6 is also discussed as an example of a protein that evolves enhanced enzymatic function in long-lived species. Finally, it is shown that several longevity-related proteins such as Cip1/p21, FOXO3, TOP2A, AKT1, RICTOR, INSR, and SIRT6 harbor posttranslational modification (PTM) sites that preferentially appear in either short- or long-lived species and provide examples of crosstalk between PTM sites. Prospects of enhancing lifespan and healthspan of humans by altering metabolism and proteoforms with drugs that mimic changes observed in long-lived species are discussed.
Keywords
- SIRT6
- aging
- long-lived mammals
- naked mole rats
- proteomics
Aging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that CHIP deficiency leads to increased levels of the insulin receptor (INSR) and reduced lifespan of worms and flies. The membrane-bound INSR regulates the insulin and IGF1 signaling (IIS) pathway and thereby defines metabolism and aging. INSR is a direct target of CHIP, which triggers receptor monoubiquitylation and endocytic-lysosomal turnover to promote longevity. However, upon proteotoxic stress conditions and during aging, CHIP is recruited toward disposal of misfolded proteins, reducing its capacity to degrade the INSR. Our study indicates a competitive relationship between proteostasis and longevity regulation through CHIP-assisted proteolysis, providing a mechanistic concept for understanding the impact of proteome imbalance on aging.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- Caenorhabditis elegans
- Drosophila melanogaster
- Endocytosis
- Humans
- Longevity
- Lysosomes
- Proteolysis
- Proteome
- Receptor, Insulin
- Signal Transduction
- Somatomedins
- Ubiquitin-Protein Ligases
- Ubiquitination
Keywords
- C. elegans
- CHIP
- DAF-2
- Drosophila
- aging
- chaperone
- insulin signaling
- longevity
- proteostasis
- ubiquitin