The E3 ubiquitin ligase Mib1 regulates Plk4 and centriole biogenesis

Abstract

BSTRACTCentrioles function as core components of centrosomes and as basal bodies for the formation of cilia and flagella. Thus, effective control of centriole numbers is essential for embryogenesis, tissue homeostasis and genome stability. In mammalian cells, the centriole duplication cycle is governed by Polo-like kinase 4 (Plk4). Here, we identify the E3 ubiquitin ligase Mind bomb (Mib1) as a new interaction partner of Plk4. We show that Mib1 localizes to centriolar satellites but redistributes to centrioles in response to conditions that induce centriole amplification. The E3 ligase activity of Mib1 triggers ubiquitylation of Plk4 on multiple sites, causing the formation of Lys11-, Lys29-and Lys48-ubiquitin linkages. These modifications control the abundance of Plk4 and its ability to interact with centrosomal proteins, thus counteracting centriole amplification induced by excess Plk4. Collectively, these results identify the interaction between Mib1 and Plk4 as a new and important element in the control of centriole homeostasis.

Regulation of centriolar satellite integrity and its physiology

“…It would be worth pointing out that whether the MIB1 ubiquitin ligase catalyses mono-ubiquitylation [58] or poly-ubiquitylation (and destabilisation) of PCM1 and CEP131/AZI1 [112] remains to be solved. In addition to centriolar satellite components (CEP131/AZI1, CEP290 and PCM1), MIB1 ubiquitylates PLK4, which leads to degradation of this protein [32]. This role of MIB1 in PLK4 stability may at least in part account for the negative role of this ubiquitin ligase in ciliogenesis as well as MIB1-mediated destabilisation of TALPID3 [32, 112].…”

“…In addition to centriolar satellite components (CEP131/AZI1, CEP290 and PCM1), MIB1 ubiquitylates PLK4, which leads to degradation of this protein [32]. This role of MIB1 in PLK4 stability may at least in part account for the negative role of this ubiquitin ligase in ciliogenesis as well as MIB1-mediated destabilisation of TALPID3 [32, 112]. Admittedly a complicated network is in action to regulate centriolar satellite integrity through the MIB1-ubiquitin pathway and its substrates.…”

“…There were reported to be 11 in 2011 [16], ~30 in 2014 [25] and >100 according to the most recent studies [26–32] (Fig. 1c).…”

Structure and function of the Mind bomb E3 ligase in the context of Notch signal transduction

“…Multiple regulators of apoptosis are modulated by Mib1 ubiquitination, including death-associated protein kinase (DAPK) and cellular FLICE-like inhibitory protein (cFLIP) [20,21]. An important role for Mib1 in centriolar biology is emerging, and suggests direct interaction and regulation of multiple factors including PLK4 (polo-like kinase 4), AZI1 (5-azacytidine induced 1), and PCM1 (pericentriolar material 1) [22,23]. In neuronal cells, Mib1 directly modulates cyclin-dependent kinase 5 (CDK5) and survival of motor neuron (SMN) protein levels independent of its well-studied role in Notch-mediated neurogenesis [17,24,25].…”

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.…”