RESUMEN
Disturbances in proteostasis are observed in many neurodegenerative diseases. This leads to activation of protein quality control to restore proteostasis, with a key role for the removal of aberrant proteins by proteolysis. The unfolded protein response (UPR) is a protein quality control mechanism of the endoplasmic reticulum (ER) that is activated in several neurodegenerative diseases. Recently we showed that the major proteolytic pathway during UPR activation is via the autophagy/lysosomal system. Here we investigate UPR induction if the other major proteolytic pathway of the ER -ER associated degradation (ERAD)-is inhibited. Surprisingly, impairment of ERAD results in decreased UPR activation and protects against ER stress toxicity. Autophagy induction is not affected under these conditions, however, a striking relocalization of the lysosomes is observed. Our data suggest that a protective UPR-modulating mechanism is activated if ERAD is inhibited, which involves lysosomes. Our data provide insight in the cross-talk between proteolytic pathways involved in ER proteostasis. This has implications for neurodegenerative diseases like Alzheimer's disease where disturbed ER proteostasis and proteolytic impairment are early phenomena in the pathology.
Asunto(s)
Alcaloides/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Degradación Asociada con el Retículo Endoplásmico/efectos de los fármacos , Técnicas de Cultivo de Célula , Estrés del Retículo Endoplásmico/fisiología , Degradación Asociada con el Retículo Endoplásmico/fisiología , Células HeLa , Humanos , Lisosomas/genética , Lisosomas/metabolismo , Microscopía Confocal , Respuesta de Proteína DesplegadaRESUMEN
The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER), the first compartment of the secretory pathway. The UPR is activated in non-tangle bearing neurons in Alzheimer's disease (AD) brain, indicating it is an early phenomenon. We found that the level of Rab6, implicated in anterograde and retrograde trafficking in the secretory pathway, is increased in brains of AD patients. Rab6 expression, closely correlated with the extent of UPR activation, is not controlled by the UPR. This suggests that Rab6 and UPR activation are both increased in response to early pathogenic changes in AD. Here we demonstrate that Rab6 modulates the UPR, increased levels inhibit whereas decreased levels augment UPR induction. Rab6 is not involved in the initial phase of the UPR; it only affects the UPR after prolonged ER stress. We propose that Rab6 is involved in the recovery from an ER stress insult. The increased Rab6 levels in AD brain in combination with UPR activation suggest that a failure to recover from ER stress may contribute to neurodegeneration in AD. The Rab6 mediated recovery pathway may provide a target to selectively inhibit the destructive pathways of the UPR.