HIPK2 Is Required for Midbody Remnant Removal Through Autophagy-Mediated Degradation

Abstract

At the end of abscission, the residual midbody forms the so-called midbody remnant (MBR), a platform affecting cell fate with emerging key role in differentiation, development, and tumorigenicity. Depending on cell type and pathophysiological context, MBRs undergo different outcomes: they can be retained, released, internalized by nearby cells, or removed through autophagy-mediated degradation. Although mechanisms underlying MBR formation, positioning, and processing have been recently identified, their regulation is still largely unknown. Here, we report that the multifunctional kinase HIPK2 regulates MBR processing contributing to MBR removal. In the process of studying the role of HIPK2 in abscission, we observed that, in addition to cytokinesis failure, HIPK2 depletion leads to significant accumulation of MBRs. In particular, we detected comparable accumulation of MBRs after HIPK2 depletion or treatment with the autophagic inhibitor chloroquine. In contrast, single depletion of the two independent HIPK2 abscission targets, extrachromosomal histone H2B and severing enzyme Spastin, only marginally increased MBR retention, suggesting that MBR accumulation is not just linked to cytokinesis failure. We found that HIPK2 depletion leads to (i) increased levels of CEP55, a key effector of both midbody formation and MBR degradation; (ii) decreased levels of the selective autophagy receptors NBR1 and p62/SQSTM1; and (iii) impaired autophagic flux. These data suggest that HIPK2 contributes to MBR processing by regulating its autophagy-mediated degradation.

Discovery and Anticancer Activity of the Plagiochilins from the Liverwort Genus Plagiochila

“…The process can be modulated with the use of histone deacetylase (HDAC) inhibitors [ 84 ], actin polymerization inhibitors [ 85 ], and various kinase inhibitors [ 86 ]. New tools are needed to dissect the process, notably to help understanding the function of the residual midbody remnant generated at the end of the process and which affects cell fate and tumorigenesis [ 87 ]. Plagiochilin A has the capacity to induce an accumulation of cancer cells (at least DU145 prostate cancer cells) connected by intercellular bridges, probably via a selective action on the sequential assembly of the endosomal sorting complexes required for transport (ESCRT) machinery [ 59 ].…”

Lysosomes at the Crossroads of Cell Metabolism, Cell Cycle, and Stemness

“…After abscission, midbody remnants are either degraded by autophagy, released into the extracellular space, or maintained and accumulated in cells, where they appear to play a role in regulating cell fate in normal and cancer stem cells [186][187][188]. Although the exact mechanism that controls midbody removal via lysosomal pathways is still not fully elucidated, recent evidence points to an important role of the HIPK2 kinase, whose inhibition leads to midbody remnant accumulation and correlates with decreased levels of the autophagy receptors NBR1 and p62/SQSTM1 [189]. In another study, FYCO1, an LC3B partner, was found to be necessary for the formation of LC3B-containing membranes around midbody remnants and FYCO1 silencing leads to midbody accumulation [190].…”