A new cellular stress response that triggers centriolar satellite reorganization and ciliogenesis

Abstract

Centriolar satellites are small, granular structures that cluster around centrosomes, but whose biological function and regulation are poorly understood. We show that centriolar satellites undergo striking reorganization in response to cellular stresses such as UV radiation, heat shock, and transcription blocks, invoking acute and selective displacement of the factors AZI1/CEP131, PCM1, and CEP290 from this compartment triggered by activation of the stress-responsive kinase p38/MAPK14. We demonstrate that the E3 ubiquitin ligase MIB1 is a new component of centriolar satellites, which interacts with and ubiquitylates AZI1 and PCM1 and suppresses primary cilium formation. In response to cell stress, MIB1 is abruptly inactivated in a p38-independent manner, leading to loss of AZI1, PCM1, and CEP290 ubiquitylation and concomitant stimulation of ciliogenesis, even in proliferating cells. Collectively, our findings uncover a new twopronged signalling response, which by coupling p38-dependent phosphorylation with MIB1-catalysed ubiquitylation of ciliogenesis-promoting factors plays an important role in controlling centriolar satellite status and key centrosomal functions in a cell stress-regulated manner.

The E3 ubiquitin ligase Mib1 regulates Plk4 and centriole biogenesis

“…This comes as a surprise, as Mib1 has previously been studied mainly in the context of Notch and nuclear factor (NF)-kB signaling (Barsi et al, 2005;Daskalaki et al, 2011;Itoh et al, 2003;Li et al, 2011;Liu et al, 2012). However, recent reports have described associations of Mib1 with centriolar satellites, small multiprotein clusters in the vicinity of centrosomes (Akimov et al, 2011;Jakobsen et al, 2011;Tollenaere et al, 2014;Villumsen et al, 2013). Here, we confirm that Mib1 localizes to centriolar satellites but additionally show that Mib1 relocates to centrioles in response to stimulation of centriole biogenesis.…”

Epb41l5 competes with Delta as a substrate for Mib1 to coordinate specification and differentiation of neurons

“…As analysis of epb41l5-deficient embryos did not appear to suggest an essential role for Epb41l5 in determining Mib1-dependent Notch signaling, we asked if instead Mib1 interacts with Epb41l5 to regulate functions of Epb41l5 through its ubiquitylation as with some other substrates of Mib1 (Cajanek et al, 2015;Kwon et al, 2013;Villumsen et al, 2013). When Epb41l5 was co-expressed with Mib1, two bands of Epb41l5 were observed (Fig.…”

Small organelle, big responsibility: the role of centrosomes in development and disease

“…Centriolar satellites have been implicated in centrosomal protein transport and ciliogenesis [118]. In addition to providing a platform for pro-ciliogenesis proteins, satellites suppress untimely cilia formation by sequestering key ciliogenesis factors [115,[119][120][121][122]. Thus, certain ciliopathy phenotypes could arise from ill-timed ciliogenesis and signalling.…”