Emerging Roles of the TRIM E3 Ubiquitin Ligases MID1 and MID2 in Cytokinesis

Abstract

Ubiquitination is a post-translational modification that consists of ubiquitin attachment to target proteins through sequential steps catalysed by activating (E1), conjugating (E2), and ligase (E3) enzymes. Protein ubiquitination is crucial for the regulation of many cellular processes not only by promoting proteasomal degradation of substrates but also re-localisation of cellular factors and modulation of protein activity. Great importance in orchestrating ubiquitination relies on E3 ligases as these proteins recognise the substrate that needs to be modified at the right time and place. Here we focus on two members of the TRIpartite Motif (TRIM) family of RING E3 ligases, MID1, and MID2. We discuss the recent findings on these developmental disease-related proteins analysing the link between their activity on essential factors and the regulation of cytokinesis highlighting the possible consequence of alteration of this process in pathological conditions.

Keywords: MID1; MID2; TRIM E3 ligase; X-linked Opitz syndrome; cytokinesis; ubiquitination.

FIGURE 1

Model for MID1 and MID2 complexes distribution during cytokinesis. MID1 and MID2 localise on the microtubules both at early (A) and late (B) telophase where they possibly hetero-interact. We propose action of MID proteins during both steps. At the central spindle, MID1 poly-ubiquitinates PP2Ac to regulate PP2A levels (i) and mono-ubiquitinates a4 to disrupt the association of a4-PP2Ac (ii). Available PP2Ac can be assembled into active PP2A holoenzymes that dephosphorylate KIF4A to control the length of spindle midzone (v). At early telophase, MID2 ubiquitinates Astrin inducing its proteasomal degradation and removal from the intercellular bridge in order to allow completion of cytokinesis (iii). BRAF35 abundance and localisation at the intercellular bridge is regulated through MID1-dependent ubiquitination using non-canonical ubiquitin linkages (K6, K27, and K29) (iv); there, BRAF35 associates with KIF4A and/or BRCA2 (vi); (vii) BRCA2 is recruited to the midbody through Filamin A and forms a complex with Cep55, Alix and Tsg101, allowing the recruitment of ESCRT-III to complete abscission. It is still unknown to what extent MID proteins activity on these substrates is interconnected and this is highlighted in the model with question marks (?). One intriguingly possibility is that KIF4A might represent the central player linking all the complexes regulate by MID1 and MID2.