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Signaling Pathways title  Autophagy

Autophagy is an adaptive process in response to cellular stress (nutrient starvation, oxidative stress, hypoxia, protein aggregation,...) to prevent cell damage and promote cell survival (1,2).

Key autophagic factors induce these autophagic mechanisms resulting in the processing and degradation of damaged material by autolysosomes (3). These factors need to be tightly controlled to ensure cellular homeostasis.

Overview of the autophagy process (4)

Signaling Pathways title  Autophagy and diseases

The dysregulation of autophagic process is now known to be involved in many pathologies (4) including :
  • infectious diseases (5)
  • cancer (6) with pro- and anti-tumoral complex roles, notably in inflammation, cell migration...
  • neurodegenerative diseases (7-8) with defects to eliminate misfolded toxic protein aggregates and damaged mitochondrion (Parkinson, SLA...) (2).
A recent study on replicative crisis suggests that autophagy is an integral component of the tumor suppressive crisis mechanism and that loss of autophagy function is required for the initiation of cancer.
Crisis was associated with an increase in the autophagy-related proteins lysosomal-associated membrane protein 1 (LAMP1), ATG5–ATG12 conjugate (for phagophore biogenesis) and the lipidated form of microtubule-associated protein 1A/1B-light chain 3 (LC3), LC3-II (for phagophore expansion), whereas the autophagy target polyubiquitin-binding protein P62 (also known as SQSTM1) was reduced (9).

Autophagic cell death restricts chromosomal instability during replicative crisis (9)

Left: The 23 pairs of chromosomes of cells in which autophagy is functioning look normal and healthy with no structural or numerical aberrations (each color represents a unique chromosome pair).

Right: the chromosomes of cells in which autophagy is not functioning bypass crisis, showing both structural and numerical aberrations, with segments added to, deleted from, and/or swapped between chromosomes - a hallmark of cancer. [Salk Institute]
(1) Mizushima N. & Komatsu M. Autophagy: renovation of cells and tissues. Cell (2011) 147(4):728-741.
(2) Klionsky, D. Jet al. A comprehensive glossary of autophagy- related molecules and processes (2nd edition). Autophagy (2011) 7(11):1273-1294.
(3) Abada A. & Elazar Z. Getting ready for building: signaling and autophagosome biogenesis. EMBO Rep. (2014) 15(8):839-852.
(4) Dikic I. & Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. (2018) 19(6):349-364.
(5) Ma Y. et al. Autophagy and cellular immune responses. Immunity (2013) 39(2): 211-227.
(6) Kimmelman A. C. & White E. Autophagy and tumor metabolism. Cell Metab. (2017) 25(5): 1037-1043
(7) Moors, T. et al. Lysosomal dysfunction and α-synuclein aggregation in Parkinson’s disease: diagnostic links. Mov Disord. (2016) 31(6): 791-801.
(8) Lee, J. K.et al. Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis. Biochim Biophys Acta. (2015) 1852(11): 2517-2524.
(9) Nassour J & al. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature. (2019).
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