Figure 1

Life and death of proteins. Proteins are synthesized as a linear amino acid chain at the ribosomes and fold into their native structure with the assistance of chaperones. Misfolded proteins in the cytosol or in cellular compartments, such as ER and mitochondria, are recognized by chaperones which support their refolding into the native structure. If misfolded proteins cannot be properly refolded, they are targeted for degradation mainly by the ubiquitin-proteasome system. For proteasomal degradation, proteins are tagged with a polyubiquitin chain and subsequently degraded by the proteasome into small peptides. Misfolded proteins of the ER or at the mitochondria are retro-translocated into the cytosol and transported to the proteasome for degradation with the help of VCP/p97. Aggregated proteins are engulfed by the autophagosome and degraded after fusion of lysosomes with the autophagosome. Degradation products of the proteasome and the autophagy pathway are mainly recycled as amino acids for protein synthesis.