The ESCRT protein Chmp4c regulates mitotic spindle checkpoint signaling

J Cell Biol. 2018 Mar 5;217(3):861-876. doi: 10.1083/jcb.201709005. Epub 2018 Jan 23.

Abstract

The mitotic spindle checkpoint delays anaphase onset in the presence of unattached kinetochores, and efficient checkpoint signaling requires kinetochore localization of the Rod-ZW10-Zwilch (RZZ) complex. In the present study, we show that human Chmp4c, a protein involved in membrane remodeling, localizes to kinetochores in prometaphase but is reduced in chromosomes aligned at the metaphase plate. Chmp4c promotes stable kinetochore-microtubule attachments and is required for proper mitotic progression, faithful chromosome alignment, and segregation. Depletion of Chmp4c diminishes localization of RZZ and Mad1-Mad2 checkpoint proteins to prometaphase kinetochores and impairs mitotic arrest when microtubules are depolymerized by nocodazole. Furthermore, Chmp4c binds to ZW10 through a small C-terminal region, and constitutive Chmp4c kinetochore targeting causes a ZW10-dependent checkpoint metaphase arrest. In addition, Chmp4c spindle functions do not require endosomal sorting complex required for transport-dependent membrane remodeling. These results show that Chmp4c regulates the mitotic spindle checkpoint by promoting localization of the RZZ complex to unattached kinetochores.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints / physiology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • HeLa Cells
  • Humans
  • Kinetochores / metabolism*
  • Mad2 Proteins / genetics
  • Mad2 Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Signal Transduction / physiology*
  • Spindle Apparatus / genetics
  • Spindle Apparatus / metabolism*

Substances

  • Cell Cycle Proteins
  • Endosomal Sorting Complexes Required for Transport
  • MAD1L1 protein, human
  • MAD2L1 protein, human
  • Mad2 Proteins
  • Nuclear Proteins
  • Snf7-3 protein, human