Figure 7.
Dual effect of the SP-C BRICHOS domain mutant leading to cellular dysfunction. At least two separate subcellular systems are affected by BRICHOS domain mutant expression: the UPR and UPS pathways. UPR: Mutant expression induces ER stress as demonstrated by ER retention of misfolded proteins, increased expression of the transcription factor XBP-1, and upregulation of chaperone genes GRP78 and HDJ2. Consequently, through undefined intermediates, caspase 3 is activated with subsequent apoptotic cell death. UPS: Persistent production of misfolded proteins overwhelms the UPS and prevents normal homeostatic degradation of proteins resulting in cellular accumulation and aggregation of proteins. Aggregation is enhanced in the case of proteins in which heteromeric association between wild type and mutant isoforms results in a dominant negative effect, as seen with SP-CΔexon4. Inhibition of UPS not only promotes the accumulation of degradation-destined proteins, but also impedes other signaling pathways including those mediated by ubiquitin. Such subcellular system dysfunction is likely to cause cell injury and, ultimately, cell death. Hatched arrows indicate undefined intermediates.