Chloroquine lysosomal degradation

Discussion in 'Hydroxychloroquine Sulfate' started by seo1, 01-Mar-2020.

  1. Real_kas Guest

    Chloroquine lysosomal degradation


    In MDA-MB-231 cells, immunolocalization and brefeldin A protein transport blocking studies revealed that there was a propensity for newly synthesized Cx43 to be transported to lysosomes. On the other hand, light and electron microscopic analysis of BICR-M1R cells showed that Cx43 gap junctions were prevalent with a subpopulation of intracellular Cx43 localized to lysosomes.

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    This accumulation leads to inhibition of lysosomal enzymes that require an acidic pH, and prevents fusion of endosomes and lysosomes. Moreover, Chloroquine inhibits autophagy as it raises the lysosomal pH, which leads to inhibition of both fusion of autophagosome with lysosome and lysosomal protein degradation 4. This inhibits lysosomal hydrolases and prevents autophagosomal fusion and degradation, which can result in apoptotic or necrotic cell death 1-4. Inhibition of chloroquine-induced apoptosis with the V-ATPase inhibitor bafilomycin A1 has been observed in several cell types 4. Autophagy is an evolutionarily conserved and strictly regulated lysosomal pathway that degrades cytoplasmic material and organelles. Autophagy is activated during stress conditions such as amino acid starvation, unfolded protein response or viral infection.

    Interestingly, lactacystin inhibition of proteosomal degradation in MDA-MB-231 cells resulted in a marked increase in phosphorylated Cx43 at the expense of non-phosphorylated Cx43, and this change corresponded with an increase in “oversized” gap junction plaques. In both cell types, Western blots revealed a notable increase in total cellular Cx43 in response to lysosome inhibitors.

    Chloroquine lysosomal degradation

    Hijacking antibody-induced CTLA-4 lysosomal degradation., CST - Chloroquine

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  7. The effects of chloroquine as a retinopathic agent, as observed by lysosomal dysfunction and RPE degradation, have been demonstrated in various animal models 21–24. We use the ability of chloroquine to increase pH 25 to both understand the general effects of chloroquine on ARPE-19, and as a model for lysosomal inhibition.

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    Chloroquine also increased expression of LC3B-II and ATG5 mRNA Figure 5B and 5C. To determine the impact of chloroquine on protein degradation and lysosome function, we examined the effects of chloroquine on p62, a protein known to be uniquely degraded by autophagy pathways. It is well known that 4-aminoquinolones have a wide range of effects. Other than modifying lysosomal acidification, they have been shown to target other molecules involved in endocytic degradation. Accumulation of chloroquine in the lysosome inhibits phospholipase A2. Chloroquine is commonly used to study the role of endosomal acidification in cellular processes 2, 3, such as the signaling of intracellular TLRs. Moreover, Chloroquine inhibits autophagy as it raises the lysosomal pH, which leads to inhibition of both fusion of autophagosome with lysosome and lysosomal protein degradation 4.

     
  8. Krotos New Member

    Chloroquine has long been used in the treatment or prevention of malaria from Plasmodium vivax, P. malariae, excluding the malaria parasite Plasmodium falciparum, for it started to develop widespread resistance to it. Chloroquine MedlinePlus Drug Information Safety Data Sheet - Pharmaceutical Chemistry SAFETY DATA SHEET Page 1 of 6 Chloroquine phosphate Revision
     
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