Under these conditions, the selective removal of proteins by CMA contributes to the elimination of altered proteins, recycling of amino acids resulting from proteolysis and selective adjustment of the proteome composition. The similarities between CMA and e-MI in the selective recognition of substrates by hsc70, has made developing methods that discriminate between CMA and e-MI necessary.Īlthough most cells display some basal level of CMA activity, several types of cellular stressors upregulate CMA, such as nutrient-deprivation, oxidative stress, proteotoxicity and lipotoxicity. An additional difference between e-MI and CMA, is that substrate unfolding is a pre-requisite for internalization in CMA, whereas folded proteins and even small oligomeric protein complexes can be internalized in the e-MI vesicles. In this process, the chaperone hsc70 also recognizes the KFERQ-like motif in the substrate proteins but delivers them to late endosomes where cargo is internalized into small vesicles that form on the surface of this organelle. Recently, selective targeting of individual proteins has also been reported in a more specific type of microautophagy, known as endosomal-microautophagy (e-MI) ( Fig. In contrast with other types of autophagy, such as macroautophagy or microautophagy that require vesicles for sequestration of the substrates degraded by these pathways, in CMA, substrate proteins are recognized individually without interfering with adjacent proteins and they are translocated into the lysosomal lumen independently of vesicular trafficking. Chaperone-Mediated Autophagy (CMA): substrate proteins recognized by hsc70 are targeted to the lysosomes and translocated across the lysosomal membrane assisted by CMA receptor LAMP2A to be degraded by lysosomal hydrolases. Endosomal microautophagy (e-MI): cytosolic content is delivered “in bulk” or upon interaction with the hsc70 chaperone to the membrane of late endosomes where multivesicular bodies (MVB) form trapping and internalizing the cargo degradation occurs upon disruption of the vesicles in the endosomal lumen or after fusion of endosomes with lysosomes. Scheme of the basic steps of three different types of mammalian autophagy: Macroautophagy: cargo such as protein aggregates, lipid droplets, organelles, are sequestered into double membrane vesicles (autophagosomes APH), which then fuse with lysosomes (autophagolysosomes APL) where cargo degradation occurs. Unfolding of the substrate proteins is followed by their translocation into lysosomes assisted by a lysosome resident hsc70 (lys-hsc70), and leads to the complete degradation of the substrate into its constitutive amino acids by the luminal proteases known as cathepsins ( Fig. A lysosomal resident form of hsp90 assures LAMP2A stability during multimerization. Substrate binding initiates multimerization of the LAMP2A monomers at the lysosomal membrane, which constitutes the basis of the CMA translocation complex. Upon binding of hsc70, substrates are targeted to the lysosomal membrane for docking at the cytosolic tail of the monomeric lysosome-associated membrane protein type-2A (LAMP2A). This motif is recognized by the constitutively expressed intracellular heat shock-cognate chaperone of 70kDa (hsc70). Selectivity is determined by the presence on the substrate proteins of a CMA targeting motif – a penta-peptide amino-acid sequence biochemically similar to KFERQ. Chaperone-mediated autophagy (CMA) refers to a very selective form of autophagy whereby a specific pool of intracellular proteins is targeted to the lysosome for degradation.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |