Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators

J Clin Invest. 2014 May;124(5):2059-70. doi: 10.1172/JCI71898. Epub 2014 Apr 1.


Cilia are critical mediators of paracrine signaling; however, it is unknown whether proteins that contribute to ciliopathies converge on multiple paracrine pathways through a common mechanism. Here, we show that loss of cilopathy-associated proteins Bardet-Biedl syndrome 4 (BBS4) or oral-facial-digital syndrome 1 (OFD1) results in the accumulation of signaling mediators normally targeted for proteasomal degradation. In WT cells, several BBS proteins and OFD1 interacted with proteasomal subunits, and loss of either BBS4 or OFD1 led to depletion of multiple subunits from the centrosomal proteasome. Furthermore, overexpression of proteasomal regulatory components or treatment with proteasomal activators sulforaphane (SFN) and mevalonolactone (MVA) ameliorated signaling defects in cells lacking BBS1, BBS4, and OFD1, in morphant zebrafish embryos, and in induced neurons from Ofd1-deficient mice. Finally, we tested the hypothesis that other proteasome-dependent pathways not known to be associated with ciliopathies are defective in the absence of ciliopathy proteins. We found that loss of BBS1, BBS4, or OFD1 led to decreased NF-κB activity and concomitant IκBβ accumulation and that these defects were ameliorated with SFN treatment. Taken together, our data indicate that basal body proteasomal regulation governs paracrine signaling pathways and suggest that augmenting proteasomal function might benefit ciliopathy patients.

Publication types

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

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology
  • Cell Line
  • Ciliary Motility Disorders / drug therapy
  • Ciliary Motility Disorders / genetics
  • Ciliary Motility Disorders / metabolism
  • Ciliary Motility Disorders / pathology
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism*
  • Isothiocyanates / pharmacology
  • Mevalonic Acid / analogs & derivatives
  • Mevalonic Acid / pharmacology
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteins / genetics
  • Proteins / metabolism*
  • Proteolysis*
  • Sulfoxides
  • Zebrafish / metabolism*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*


  • Anticarcinogenic Agents
  • BBS4 protein, human
  • BBS4 protein, mouse
  • Bbs1 protein, human
  • Bbs1 protein, mouse
  • I kappa B beta protein
  • I-kappa B Proteins
  • Isothiocyanates
  • Microtubule-Associated Proteins
  • OFD1 protein, human
  • OFD1 protein, mouse
  • Proteins
  • Sulfoxides
  • Zebrafish Proteins
  • mevalonolactone
  • Proteasome Endopeptidase Complex
  • sulforaphane
  • Mevalonic Acid