Pathophysiology of Primary Cilia: Signaling and Proteostasis Regulation

Abstract

Primary cilia are microtubule-based, non-motile sensory organelles present in most types of growth-arrested eukaryotic cells. They are transduction hubs that receive and transmit external signals to the cells in order to control growth, differentiation and development. Mutations of genes involved in the formation, maintenance or disassembly of ciliary structures cause a wide array of developmental genetic disorders, also known as ciliopathies. The primary cilium is formed during G1 in the cell cycle and disassembles at the G2/M transition. Following the completion of the cell division, the cilium reassembles in G1. This cycle is finely regulated at multiple levels. The ubiquitin-proteasome system (UPS) and the autophagy machinery, two main protein degradative systems in cells, play a fundamental role in cilium dynamics. Evidence indicate that UPS, autophagy and signaling pathways may act in synergy to control the ciliary homeostasis. However, the mechanisms involved and the links between these regulatory systems and cilium biogenesis, dynamics and signaling are not well defined yet. Here, we discuss the reciprocal regulation of signaling pathways and proteolytic machineries in the control of the assembly and disassembly of the primary cilium, and the impact of the derangement of these regulatory networks in human ciliopathies.

Autophagy and the primary cilium in cell metabolism: What’s upstream?

“…The past several years have illuminated the cross-talk between the primary cilium and the two major cellular catabolic pathways, i.e., the autophagic pathway and the ubiquitin proteasomesystem (UPS) ( Orhon et al, 2015 ; Pampliega and Cuervo, 2016 ; Boukhalfa et al, 2019 ; Wiegering et al, 2019 ; Morel et al, 2021 ; Morleo et al, 2022 ; Senatore et al, 2022 ). Many studies have demonstrated that autophagy is engaged in the regulation of ciliogenesis by controlling the expression of factors such as IFT20 ( Pampliega et al, 2013 ), OFD1 ( Tang et al, 2013 ), MYH9/myosin 2 ( Yamamoto et al, 2021 ), CP110 ( Liu et al, 2021 ) or Kif19A ( Arora et al, 2020 ).…”

“…While not directly related to the topic of the review, it is important to keep in mind that a complex crosstalk exist between the primary cilium and the ubiquitin proteasome system (UPS) ( Orhon et al, 2015 ; Pampliega and Cuervo, 2016 ; Boukhalfa et al, 2019 ; Wiegering et al, 2019 ; Morel et al, 2021 ; Morleo et al, 2022 ; Senatore et al, 2022 ) and between autophagy and the UPS ( Kwon and Ciechanover, 2017 ; Pohl and Dikic, 2019 ). The UPS plays an important role for controlling ciliogenesis and disassembly of the primary cilium ( Kim et al, 2010 ; Wheway et al, 2015 ).…”

“…The specific aim of the present review is to present the importance of the cross-talk between autophagy and the primary cilium in the control of metabolism and also to highlight stimuli and signaling pathways that emanate from the primary cilium to regulate autophagy. Readers interested in a deeper discussion on the cross-talk between the primary cilium and autophagy and/or on the role of primary cilium in regulating proteostasis can consult recent reviews on these topics ( Orhon et al, 2015 ; Pampliega and Cuervo, 2016 ; Boukhalfa et al, 2019 ; Wiegering et al, 2019 ; Morel et al, 2021 ; Morleo et al, 2022 ; Senatore et al, 2022 ).…”

Golgi Dysfunctions in Ciliopathies

“…While IFT20 was colocalized both at the cis-Golgi and scattered in vesicles throughout the cytoplasm in complete medium, serum starvation resulted in a restricted distribution of the protein in the GA, only in VPS15-deficient patient cells, suggesting a defect in the release of IFT20 positive vesicles from the cis-Golgi to the primary cilium [ 5 ]. The interplay between ciliogenesis and autophagy has been pointed out [ 51 ]. As in Vps15-depleted cells, autophagy flux is compromised (increase in the accumulation of adaptor protein p62, LC3 and Lamp2 positive vesicles); we can thus hypothesize that the loss of VPS15 could affect ciliogenesis through an abnormal autophagic process [ 50 ].…”

Proteolysis at work: when time matters for a sensory organelle

“…Components of the UPS, including E2 ubiquitin‐conjugating enzymes, E3 ubiquitin ligases and deubiquitylating enzymes (DUBs) have been identified as resident of—or closely associated to—the ciliary compartment. Here, the ubiquitin‐directed proteolysis of key substrates is functionally relevant for cilium dynamics [ 1 ] . The review by Habeck and Schweiggert describes the current knowledge of the role of the UPS in primary ciliogenesis, with a special focus on the timing of ubiquitylation events underlying cilium formation and disassembly.…”