LUBAC regulates ciliogenesis by promoting CP110 removal from the mother centriole

Abstract

Primary cilia transduce diverse signals in embryonic development and adult tissues. Defective ciliogenesis results in a series of human disorders collectively known as ciliopathies. The CP110–CEP97 complex removal from the mother centriole is an early critical step for ciliogenesis, but the underlying mechanism for this step remains largely obscure. Here, we reveal that the linear ubiquitin chain assembly complex (LUBAC) plays an essential role in ciliogenesis by targeting the CP110–CEP97 complex. LUBAC specifically generates linear ubiquitin chains on CP110, which is required for CP110 removal from the mother centriole in ciliogenesis. We further identify that a pre-mRNA splicing factor, PRPF8, at the distal end of the mother centriole acts as the receptor of the linear ubiquitin chains to facilitate CP110 removal at the initial stage of ciliogenesis. Thus, our study reveals a direct mechanism of regulating CP110 removal in ciliogenesis and implicates the E3 ligase LUBAC as a potential therapy target of cilia-associated diseases, including ciliopathies and cancers.

Cilia regeneration requires an RNA splicing factor from the ciliary base

“…How does PRP-8 act from the ciliary base to promote cilium formation and regeneration? Recent studies reported that PRPF8 functions as the receptor of linear ubiquitin chains at the ciliary base to facilitate CP110-CEP97 complex removal at the initial stage of ciliogenesis , Shen, Yuan et al 2022. Such a role of PRPF8 may apply to cilium regeneration from the existing middle ciliary segment, which suggests that PRPF8 must play additional roles from the ciliary base.…”

Proteolytic control in ciliogenesis: Temporal restriction or early initiation?

“…CP110 is prone to a remarkably complex regulatory network that involves four ubiquitin E3 ligases (SCF CyclinF , EDD1-DYRK2-DDB1-VPRBP, LUBAC and NEURL4), two DUBs (USP33 and OTULIN) and two kinases (TTBK2 and MARK4). [32][33][34][35][36][37] In cycling cells, CP110 becomes ubiquitylated for proteasomal degradation by SCF CyclinF , another Cullin-RING ligase that utilises CyclinF as a substrate receptor. [32] This process is restricted to the G 2 /M-phase of the cell cycle, which is at least partially due to the counteracting activity of the DUB USP33 that deubiquitylates and thereby protects CP110 during S and early G 2 .…”

“…CP110 is prone to a remarkably complex regulatory network that involves four ubiquitin E3 ligases (SCF CyclinF , EDD1‐DYRK2‐DDB1‐VPRBP, LUBAC and NEURL4), two DUBs (USP33 and OTULIN) and two kinases (TTBK2 and MARK4). [ 32–37 ]…”

“…Finally, CP110 is regulated by another E3 ligase complex called LUBAC (linear ubiquitin chain assembly complex) that catalyses linear ubiquitin chains (linked via the N‐terminal amino group of ubiquitin) on CP110. [ 34 ] In contrast to the above‐mentioned processes, this modification does not induce proteasomal degradation of CP110 but instead promotes its binding to PRPF8, which leads to CP110's removal from centrosomes and thereby facilitates ciliogenesis. Interestingly, a mass spec approach using GST‐tagged linear tetraubiquitin revealed also EDD1 as a potential binding factor for linear ubiquitin chains, [ 34 ] which indicates a potential connection to the EDD1‐DYRK2‐DDB1‐VPRBP pathway.…”

“…[ 34 ] In contrast to the above‐mentioned processes, this modification does not induce proteasomal degradation of CP110 but instead promotes its binding to PRPF8, which leads to CP110's removal from centrosomes and thereby facilitates ciliogenesis. Interestingly, a mass spec approach using GST‐tagged linear tetraubiquitin revealed also EDD1 as a potential binding factor for linear ubiquitin chains, [ 34 ] which indicates a potential connection to the EDD1‐DYRK2‐DDB1‐VPRBP pathway. It is yet not clear whether this process is also active in cycling cells.…”