AKTIP interacts with ESCRT I and is needed for the recruitment of ESCRT III subunits to the midbody

Abstract

To complete mitosis, the bridge that links the two daughter cells needs to be cleaved. This step is carried out by the endosomal sorting complex required for transport (ESCRT) machinery. AKTIP, a protein discovered to be associated with telomeres and the nuclear membrane in interphase cells, shares sequence similarities with the ESCRT I component TSG101. Here we present evidence that during mitosis AKTIP is part of the ESCRT machinery at the midbody. AKTIP interacts with the ESCRT I subunit VPS28 and forms a circular supra-structure at the midbody, in close proximity with TSG101 and VPS28 and adjacent to the members of the ESCRT III module CHMP2A, CHMP4B and IST1. Mechanistically, the recruitment of AKTIP is dependent on MKLP1 and independent of CEP55. AKTIP and TSG101 are needed together for the recruitment of the ESCRT III subunit CHMP4B and in parallel for the recruitment of IST1. Alone, the reduction of AKTIP impinges on IST1 and causes multinucleation. Our data altogether reveal that AKTIP is a component of the ESCRT I module and functions in the recruitment of ESCRT III components required for abscission.

Phase Separation in the Nucleus and at the Nuclear Periphery during Post-Mitotic Nuclear Envelope Reformation

“…Recently, a new factor, named AKTIP, was discovered that intercepts the concepts of nuclear envelope, ESCRTs, and telomere function [ 97 , 98 , 99 ]. AKTIP deficiency generates telomere fragility and has the singularity as a telomeric protein to be enriched at the nuclear envelope [ 97 , 99 , 100 ].…”

“…AKTIP deficiency generates telomere fragility and has the singularity as a telomeric protein to be enriched at the nuclear envelope [ 97 , 99 , 100 ]. AKTIP has sequence similarity with the protein TSG101, a tumor susceptibility gene that functions as ESCRT I in viral budding and cytokinesis [ 83 ], and AKTIP acts in association with ESCRTs in cytokinesis [ 98 ]. In vivo, AKTIP assembles into discrete foci at the nuclear envelope [ 97 , 98 , 99 ] and contains two disordered regions that may be potentially involved in LLPS.…”

“…AKTIP has sequence similarity with the protein TSG101, a tumor susceptibility gene that functions as ESCRT I in viral budding and cytokinesis [ 83 ], and AKTIP acts in association with ESCRTs in cytokinesis [ 98 ]. In vivo, AKTIP assembles into discrete foci at the nuclear envelope [ 97 , 98 , 99 ] and contains two disordered regions that may be potentially involved in LLPS. Given the above, it would be tempting to speculate that phase separation can contribute to AKTIP activities at the nuclear envelope.…”

The Abscission Checkpoint: A Guardian of Chromosomal Stability

“…Interestingly, in Drosophila which has no Cep55, Alix and Tsg101 recruitment to the midbody is promoted by the centralspindlin component Pavarotti (the human Mklp1 homologue; [ 35 ]). Furthermore, localization of the ESCRT-I component AKTIP to the midbody depends on Mklp1 but is independent of Cep55 in human cells [ 36 ].…”

Comprehensive analysis of the human ESCRT-III-MIT domain interactome reveals new cofactors for cytokinetic abscission

“…In a parallel pathway, CEP55 binds the TSG101 subunit of ESCRT-I/II complexes (Morita et al, 2007, Carlton and Martin-Serrano, 2007, Christ et al, 2016, Lee et al, 2008, again leading to ESCRT-III recruitment. ESCRT-III recruitment is also promoted by the midbody protein SEPT9 (Karasmanis et al, 2019), and other CEP55-independent pathways (Merigliano et al, 2021, Addi et al, 2020. Humans express 12 homologous ESCRT-III proteins that fall into eight different families, termed CHMP1-7 and IST1.…”