Degradation of Misfolded Secretory and Membrane Proteins and Associated Diseases

Protein homeostasis is maintained through a balance among protein synthesis, folding, assembly and degradation. The latter is crucial also to prevent accumulation of misfolded products in the cell. The conjugation to ubiquitin marks proteins for degradation by the proteasome. Secretory and membrane proteins are monitored for proper folding and oligomerization in the endoplasmic reticulum (ER). In this compartment, defective proteins are recognised and targeted to the proteasome in a process called ER-associated protein degradation or ERAD. A first step of retrotranslocation across the ER membrane to the cytosol is required. Ubiquitylation is carried out by ER enzymes and is also functionally intertwined with retrotranslocation. Malfunctioning of ERAD machinery or accumulation of folding-defective proteins in the ER is associated with various human diseases ranging from neurodegenerative disorders to cancer. The design of drugs that meliorate ERAD or promote protein folding could provide new therapeutic strategies against these diseases.