Selective autophagy: talking with the UPS

Abstract

Far from now are the days when investigators raced to identify the proteolytic system responsible for the degradation of their favorite protein. Nowadays, it is well accepted that a given protein can be degraded by different systems depending on factors such as cell type, cellular conditions, or functionality of each proteolytic pathway. The realization of this sharing of substrates among pathways has also helped to unveil deeper levels of communication among the different proteolytic systems. Thus, cells often respond to blockage of one degradative mechanism by upregulating any of the other available pathways. In addition, effectors and regulators of one proteolytic system can be degraded by a different proteolytic pathway that exerts, in this way, a regulatory function. In this mini review, we describe the different levels of cross-talk among autophagic pathways and the ubiquitin/proteasome system. We also provide examples of how this proteolytic communication is used for compensatory purposes in different pathological conditions and discuss the possible therapeutic potential of targeting the modulators of the cross-talk among proteolytic pathways.

Figure 1. Intracellular proteolytic systems cross-talk

Recent studies support many levels of functional interaction and cross-talk among the main proteolytic systems in the cell: the ubiquitin proteasome system (UPS) and the different autophagic pathways (macroautophagy, microautophagy and chaperone-mediated autophagy (CMA)). Some of the already identified levels of cross-talk are highlighted and discussed in the text.

Figure 2. Compensatory mechanisms in intracellular proteolysis

Changes in the activity of one proteolytic system impact the activity of the other systems. So far, most of the changes described are of compensatory nature whereby blockage of one pathway (marked with a red cross) leads to upregulation of another one (marked with a green arrow). However, there are also instances in which blockage of one pathway also interferes with the functionality of another. This proteolytic crosstalk may be influenced by many factors, as the ones shown in the cloud.