NudCL2 is an autophagy receptor that mediates selective autophagic degradation of CP110 at mother centrioles to promote ciliogenesis

Abstract

Primary cilia extending from mother centrioles are essential for vertebrate development and homeostasis maintenance. Centriolar coiled-coil protein 110 (CP110) has been reported to suppress ciliogenesis initiation by capping the distal ends of mother centrioles. However, the mechanism underlying the specific degradation of mother centriole-capping CP110 to promote cilia initiation remains unknown. Here, we find that autophagy is crucial for CP110 degradation at mother centrioles after serum starvation in MEF cells. We further identify NudC-like protein 2 (NudCL2) as a novel selective autophagy receptor at mother centrioles, which contains an LC3-interacting region (LIR) motif mediating the association of CP110 and the autophagosome marker LC3. Knockout of NudCL2 induces defects in the removal of CP110 from mother centrioles and ciliogenesis, which are rescued by wild-type NudCL2 but not its LIR motif mutant. Knockdown of CP110 significantly attenuates ciliogenesis defects in NudCL2-deficient cells. In addition, NudCL2 morphants exhibit ciliation-related phenotypes in zebrafish, which are reversed by wild-type NudCL2, but not its LIR motif mutant. Importantly, CP110 depletion significantly reverses these ciliary phenotypes in NudCL2 morphants. Taken together, our data suggest that NudCL2 functions as an autophagy receptor mediating the selective degradation of mother centriole-capping CP110 to promote ciliogenesis, which is indispensable for embryo development in vertebrates.

Pathophysiology of Primary Cilia: Signaling and Proteostasis Regulation

“…During starvation, the autophagic degradation of CP110 mediated by NudC-like protein 2 (NudCL2), a selective autophagy receptor at the mother centriole, induces cilium formation. This mechanism was confirmed also in Zebrafish models, where depletion of NudCL2 generates a ciliary phenotype that is rescued by CP110 depletion ( Liu et al, 2021 ).…”

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 ). As such, the word “ciliophagy” has been adequately introduced to designate the selective degradation of ciliary proteins by the autophagic pathway ( Cloonan et al, 2014 ).…”

NudCL2 is essential for cytokinesis by stabilizing RCC2 with Hsp90 at the midbody

“…NudCL2 also plays important roles for centriole duplication and sister chromatid cohesion by stabilizing the HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2) and the cohesin subunits during S-phase and prometaphase, respectively 32,47 . Additionally, NudCL2 acts as an autophagy receptor to promote ciliogenesis by mediating the selective degradation of centrosomal protein of 110 kDa (CP110) at mother centrioles 48 . However, whether NudCL2 is required for cytokinesis is still unknown.…”