Posttranslational modifications and proteinopathies: How guardians of the proteome are defeated

Abstract

Protein folding is one of the fundamental processes in life and therefore needs to be tightly regulated. Many cellular quality control systems are in place to ensure that proteostasis is optimally adjusted for a changing environment, facilitating protein folding, translocation and degradation. These systems include the molecular chaperones and the major protein degradation systems, namely the ubiquitin proteasome system and autophagy. However, the capacity of the quality control systems can be exhausted and protein misfolding and aggregation, including the formation of amyloids, can occur as a result of ageing, mutations or exogenous influences. There are many known diseases in which protein misfolding and aggregation can be the underlying cause of the pathological condition; these are referred to as proteinopathies. Over the last decade, it has become clear that posttranslational modifications can govern and modulate protein folding, and that aberrant posttranslational modifications can cause or contribute to proteinopathies. This review provides an overview of protein folding and misfolding and the role of the major protein quality control systems. It focusses on different posttranslational modifications and gives examples of how these posttranslational modifications can alter protein folding and cause or accompany proteinopathies.