Aggresome pathway components

The aggresome pathway is a critical cellular mechanism designed to sequester and clear misfolded protein aggregates that escape degradation by the ubiquitin-proteasome system (UPS). When the UPS is overwhelmed, misfolded proteins are polyubiquitinated and recognized by Histone deacetylase 6 (HDAC6), which serves as a molecular linker to the dynein motor complex. These proteins are then transported along microtubules to the microtubule-organizing center (MTOC) to form a single large inclusion called an aggresome, which is subsequently degraded via a specialized autophagic process known as aggrephagy (Source: PubMed, PMID: 11500494). This pathway is particularly vital for the survival of cancer cells, such as multiple myeloma, which produce high levels of paraproteins and are highly dependent on efficient protein clearance (Source: Journal of Hematology & Oncology, 2017). Therapeutic strategies often involve the use of HDAC6 inhibitors in combination with proteasome inhibitors like bortezomib to induce synergistic proteotoxic stress and cell death (Source: Clinical Cancer Research, 2011). Beyond oncology, the aggresome pathway is a major focus in neurodegenerative research, as the failure to clear protein aggregates is a hallmark of diseases like Parkinson's, Alzheimer's, and Amyotrophic Lateral Sclerosis (Source: Nature Reviews Molecular Cell Biology, 2018).

Other names

Aggresome-autophagy pathwayAggrephagy pathwayProtein aggregate clearance pathwayHDAC6-mediated aggresome pathway

Inhibition of key components like Histone deacetylase 6 (HDAC6) prevents the dynein-dependent transport of misfolded proteins to the aggresome, leading to the accumulation of cytotoxic protein aggregates and induction of apoptosis, particularly when the proteasome is simultaneously inhibited.