MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis

J Cell Sci. 2005 Mar 1;118(Pt 5):1007-20. doi: 10.1242/jcs.01676.

Abstract

Chaperonins are multisubunit, cylinder-shaped molecular chaperones involved in folding newly synthesized polypeptides. Here we show that MKKS/BBS6, one of several proteins associated with Bardet-Biedl syndrome (BBS), is a Group II chaperonin-like protein that has evolved recently in animals from a subunit of the eukaryotic chaperonin CCT/TRiC, and diverged rapidly to acquire distinct functions. Unlike other chaperonins, cytosolic BBS6 does not oligomerize, and the majority of BBS6 resides within the pericentriolar material (PCM), a proteinaceous tube surrounding centrioles. During interphase, BBS6 is confined to the lateral surfaces of the PCM but during mitosis it relocalizes throughout the PCM and is found at the intercellular bridge. Its predicted substrate-binding apical domain is sufficient for centrosomal association, and several patient-derived mutations in this domain cause mislocalization of BBS6. Consistent with an important centrosomal function, silencing of the BBS6 transcript by RNA interference in different cell types leads to multinucleate and multicentrosomal cells with cytokinesis defects. The restricted tissue distribution of BBS6 further suggests that it may play important roles in ciliated epithelial tissues, which is consistent with the probable functions of BBS proteins in basal bodies (modified centrioles) and cilia. Our findings provide the first insight into the nature and cellular function of BBS6, and shed light on the potential causes of several ailments, including obesity, retinal degeneration, kidney dysfunction and congenital heart disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bardet-Biedl Syndrome / metabolism*
  • COS Cells
  • Cell Division
  • Centrifugation, Density Gradient
  • Centrioles / metabolism
  • Centrosome / metabolism
  • Centrosome / ultrastructure*
  • Cilia / metabolism
  • Cytokinesis*
  • Dyneins / chemistry
  • Epithelium / metabolism
  • Gene Silencing
  • Green Fluorescent Proteins / metabolism
  • Group II Chaperonins
  • HeLa Cells
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • In Situ Hybridization
  • Mice
  • Microscopy, Fluorescence
  • Molecular Chaperones / metabolism
  • Molecular Chaperones / physiology*
  • Molecular Sequence Data
  • Mutation
  • NIH 3T3 Cells
  • Obesity / metabolism*
  • Phylogeny
  • Plasmids / metabolism
  • Protein Binding
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Sequence Homology, Amino Acid
  • Sucrose / pharmacology
  • Transfection

Substances

  • MKKS protein, human
  • Molecular Chaperones
  • RNA, Small Interfering
  • Green Fluorescent Proteins
  • Sucrose
  • Group II Chaperonins
  • Dyneins