Chaperone-directed ubiquitylation maintains proteostasis at the expense of longevity

نویسندگان

  • Wojciech Pokrzywa
  • Robin Lorenz
  • Thorsten Hoppe
چکیده

The integrity of the cellular proteome is supported by quality control networks, which govern protein synthesis, folding, and degradation. It is generally accepted that an age-related decline in protein homeostasis (proteostasis) contributes to protein aggregation diseases. However, the mechanistic principles underlying proteostasis imbalance and the impact on life expectancy are not well understood. We recently demonstrated that this interrelation is affected by chaperone-directed ubiquitylation, shifting the amount of the conserved DAF-2/insulin receptor both in Caenorhabditis elegans and Drosophila melanogaster. The ubiquitin ligase CHIP either targets the membrane bound insulin receptor or misfolded proteins for degradation, which depends on the cellular proteostasis status. Increased proteotoxicity triggers chaperone-assisted redirection of CHIP toward protein aggregates, limiting its capacity to degrade the insulin receptor and prevent premature aging. In light of these findings, we discuss a new concept for understanding the impact of proteome imbalance on longevity risk.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

CHIPped balance of proteostasis and longevity

Aging is modulated by environmental and physiological changes, involving genetic pathways that are conserved from yeast cells to mammalian organisms. Notably, Insulin/IGF-like signaling (IIS) contributes to the integrity of the cellular proteome and thus defines the aging process and the onset of age-related diseases. The insulin receptor named DAF-2 in C. elegans or INSR in mammals regulates f...

متن کامل

Life and destruction: ubiquitin-mediated proteolysis in aging and longevity

The ubiquitin/proteasome system (UPS) regulates the turnover of improperly folded and damaged proteins to maintain protein homeostasis (proteostasis), cellular function, and viability. It is commonly thought that an age-related impairment of the UPS affects general proteostasis networks, which causes enhanced protein aggregation and contributes to normal aging. Recent studies identified the exi...

متن کامل

Chaperones in Neurodegeneration.

UNLABELLED Cellular protein homeostasis (proteostasis) maintains the integrity of the proteome and includes protein synthesis, folding, oligomerization, and turnover; chaperone proteins assist with all of these processes. Neurons appear to be especially susceptible to failures in proteostasis, and this is now increasingly recognized as a major origin of neurodegenerative disease. This review, b...

متن کامل

The homeodomain-interacting protein kinase HPK-1 preserves protein homeostasis and longevity through master regulatory control of the HSF-1 chaperone network and TORC1-restricted autophagy in Caenorhabditis elegans

An extensive proteostatic network comprised of molecular chaperones and protein clearance mechanisms functions collectively to preserve the integrity and resiliency of the proteome. The efficacy of this network deteriorates during aging, coinciding with many clinical manifestations, including protein aggregation diseases of the nervous system. A decline in proteostasis can be delayed through th...

متن کامل

Organismal proteostasis: role of cell-nonautonomous regulation and transcellular chaperone signaling.

Protein quality control is essential in all organisms and regulated by the proteostasis network (PN) and cell stress response pathways that maintain a functional proteome to promote cellular health. In this review, we describe how metazoans employ multiple modes of cell-nonautonomous signaling across tissues to integrate and transmit the heat-shock response (HSR) for balanced expression of mole...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 6  شماره 

صفحات  -

تاریخ انتشار 2017