Chaperone-mediated autophagy

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Chaperone-mediated autophagy (CMA) is a lysosomal pathway leading to the breakdown of cytosolic proteins during times of prolonged starvation[1]. It is one of the more selective forms of autophagy due to its reliance on specific targeting motifs on its target proteins. This process is much more specific than other types of autophagy, like macroautophagy, which relies on randomly forming de novo double membrane vesicles, called autophagosomes, around areas of cytoplasm and its associated proteins and organelles for degradation[2]. Also, in contrast to other forms of autophagy, the proteins to be degraded are not engulfed byautophagosomes which fuse to lysosomes, instead they are translocated across the lysosomal membrane in a receptor-mediated process[3].

Selectivity

At the start of starvation, the normal response of the cell is to activate macroautophagy pathways to degrade random portions of the cytosol. However, if starvation occurs for more than 6-8 hours then a switch is made to the more selective CMA. As previously mentioned, a five residue long motif in the polypeptide sequence is responsible CMA’s selectivity. The five-residue motif is fairly specific in its requirements, however, there is room for flexibility. The motif must contain a Glutamate (Q) at one end, one acidic residue (D or E), one basic residue (K or R), one hydrophobic residue (F, I, L or V) and one residue that can be either basic or hydrophobic (so long as it is not negative)[4]. This targeting motif does not need to be in a position where it can be easily accessed on the protein, most proteins need partial unfolding for the motif to be reached[5]. While this motif is shared by all proteins that are degraded by CMA, the mere presence of this motif does not guarantee that the protein is a candidate for CMA[6]. The increased specificity of CMA allows the cell to preserve more vital components, to allow it to continue functioning for a long as possible, which would not be the case if macroautophagy were its only response, as this process may degrade essential components of the cell, hindering it.

References

  1. Dice J. Chaperone-Mediated Autophagy. Autophagy. 2007;3(4):295-299.
  2. Mizushima N, Ohsumi Y, Yoshimori T. Autophagosome Formation in Mammalian Cells. Cell Structure and Function. 2002;27(6):421-429.
  3. Lodish H. Molecular cell biology. New York: Freeman - MacMillan; 2016. 661-665
  4. Wang D, Peng Z, Ren G, Wang G. The different roles of selective autophagic protein degradation in mammalian cells. Oncotarget. 2015;6(35): 37098–37116
  5. Lodish H. Molecular cell biology. New York: Freeman - MacMillan; 2016. 661-665
  6. Lodish H. Molecular cell biology. New York: Freeman - MacMillan; 2016. 661-665
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