The Role of Primary Cilia in the Crosstalk between the Ubiquitin⁻Proteasome System and Autophagy

Abstract

Protein degradation is a pivotal process for eukaryotic development and homeostasis. The majority of proteins are degraded by the ubiquitin⁻proteasome system and by autophagy. Recent studies describe a crosstalk between these two main eukaryotic degradation systems which allows for establishing a kind of safety mechanism. If one of these degradation systems is hampered, the other compensates for this defect. The mechanism behind this crosstalk is poorly understood. Novel studies suggest that primary cilia, little cellular protrusions, are involved in the regulation of the crosstalk between the two degradation systems. In this review article, we summarise the current knowledge about the association between cilia, the ubiquitin⁻proteasome system and autophagy.

Keywords: BBS4; GLI; IFT; OFD1; RPGRIP1L; hedgehog; mTOR; neurodegenerative diseases; protein aggregation.

Figure 1

Overview of ubiquitin–proteasome system (UPS) protein degradation, autophagy and primary cilium structure. (A) The ubiquitin–proteasome system. The ubiquitinated substrate is recognised by the 19S regulatory subunit of the 26S proteasome and gets degraded or proteolytically processed by the 20S subunit of the 26S proteasome. (B) Autophagy starts with the formation of phagophores which subsequently elongate to finally develop into autophagosomes. During autophagosome formation, target proteins and structures become enclosed in the autophagosomes. These autophagosomes fuse with lysosomes and the hydrolases of the lysosomes degrade the target proteins and structures. (C) Primary cilia consist of a microtubule scaffold called axoneme. The axoneme is surrounded by the ciliary membrane and grows out of the basal body. The basal body is a modified mother centriole that is connected to the daughter centriole by interconnecting fibres. The basal body is attached to the ciliary membrane in the region of the ciliary pocket via transition fibres. The transition zone, with its Y-links, is located at the proximal part of the axoneme.

Figure 2

Cilia-mediated HH, PDGFRα and TGFβ signalling. (A) Without the HH ligand, the receptor PTC inhibits ciliary entry of SMO. GLI2-FL and GLI3-FL are proteolytically processed into the repressor forms GLI2-R and GLI3-R by the ciliary proteasome. They translocate into the nucleus and inhibit HH target gene expression. In the presence of HH, HH binds to its receptor PTC and the HH/PTC complex leaves the cilium. SMO enters the cilium and GLI2-FL and GLI3-FL become activated and, in turn, initiate HH target gene expression. (B) PDGF-AA binds to the ciliary receptor PDGFRα and activates AKT signalling or the MEK1/2–ERK1/2 signalling cascade. TGFβ binds to a heterotetrameric receptor composed of TGFβ-RI and TGFβ-RII in the ciliary membrane. At the base of cilia, the signal is transduced via different SMAD proteins.

Figure 3

Complex network of the cilia-related crosstalk between the UPS and autophagy. Autophagy is able to regulate overall proteasomal activity in a positive or negative manner via BBS4 or OFD1. In addition, autophagy regulates ciliogenesis via OFD1 and/or IFT20 and thereby affects ciliary signalling. In turn, several cilia-mediated signalling cascades, like HH and mTOR signalling, modulate autophagy. Moreover, mTOR signalling regulates the overall proteasomal activity either positively or negatively (which is a matter of fierce debate). Additional cilia-associated proteins, like IFT20 or RPGRIP1L, regulate ciliogenesis as well as autophagy, whereby RPGRIP1L is also able to regulate the activity of the ciliary proteasome.