LRIF1 interacts with HP1α to coordinate accurate chromosome segregation during mitosis

Abstract

Heterochromatin protein 1α (HP1α) regulates chromatin specification and plasticity during cell fate decision. Different structural determinants account for HP1α localization and function during cell division cycle. Our earlier study showed that centromeric localization of HP1α depends on the epigenetic mark H3K9me3 in interphase, while its centromeric location in mitosis relies on uncharacterized PXVXL-containing factors. Here, we identified a PXVXL-containing protein, ligand-dependent nuclear receptor-interacting factor 1 (LRIF1), which recruits HP1α to the centromere of mitotic chromosomes and its interaction with HP1α is essential for accurate chromosome segregation during mitosis. LRIF1 interacts directly with HP1α chromoshadow domain via an evolutionarily conserved PXVXL motif within its C-terminal. Importantly, the LRIF1-HP1α interaction is critical for Aurora B activity in the inner centromere. Mutation of PXVXL motif of LRIF1 leads to defects in HP1α centromere targeting and aberrant chromosome segregation. These findings reveal a previously unrecognized direct link between LRIF1 and HP1α in centromere plasticity control and illustrate the critical role of LRIF1‒HP1α interaction in orchestrating accurate cell division.

HP1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics

“…Our findings with acute degradation of HP1α reveal a three-fold increase in both misalignment and missegregation, which were mostly observed anaphase bridges. Our results are in agreement with HP1α interacting with LRIF at the centromere, which when perturbed results in similar misalignment and missegregation (Akram et al, 2018). However, further work is required to determine if chromosome misalignment is due to a biochemical pathway or mechanical pathway at the centromere and if whole chromosome mechanics controlled by HP1α influence proper segregation.…”

“…The capacity of HP1α to drive liquid-liquid phase separation (Larson et al, 2017; Strom et al, 2017) could also contribute to altered chromatin organization and mechanics, given the emerging evidence for links between phase separation and nuclear mechanics (Shin et al, 2018). These mechanisms could also affect mechanics in mitotic chromosomes, where HP1α is also present (Akram et al, 2018; Serrano et al, 2009). The role of HP1α in controlling chromatin mechanics during both interphase and mitosis, as well as the functions of HP1α-mediated chromatin mechanics, remain to be determined.…”

Phase separation drives decision making in cell division

“…Structurally, the centromere is comprised of three layers: an inner centromere that consists of a specialized layer of chromatin with kinase activity, an outer plate that consists of tightly packed centromeric nucleosomes, and an outermost corona containing the mitotic motor, CENP-E, and other proteins (3,9,40). The inner centromere, which is comprised of Aurora B, INCENP, borealin, and survivin, is a specialized region that promotes cohesion, the regulation of kinetochores, and the assembly of specialized chromatin and mechano-sensation of spindle-pulling forces (49,58,59). Inner centromere kinase activity is driven by LLPS via a molecular condensate scaffold built by the chromosome passenger complex (60).…”

Acetylation of ezrin regulates membrane–cytoskeleton interaction underlying CCL18-elicited cell migration

“…The pull-down assay was performed as previously described ( Akram et al, 2018 ). Briefly, purified GST-tagged protein-bound Sepharose beads were used as affinity matrix to incubate with purified His-tagged proteins.…”