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Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators
Yangfan P. Liu, … , Brunella Franco, Nicholas Katsanis
Yangfan P. Liu, … , Brunella Franco, Nicholas Katsanis
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(5):2059-2070. https://doi.org/10.1172/JCI71898.
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Research Article Cell biology

Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators

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Abstract

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.

Authors

Yangfan P. Liu, I-Chun Tsai, Manuela Morleo, Edwin C. Oh, Carmen C. Leitch, Filomena Massa, Byung-Hoon Lee, David S. Parker, Daniel Finley, Norann A. Zaghloul, Brunella Franco, Nicholas Katsanis

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Figure 4

Ciliopathy proteins interact with proteasomal components and regulate proteasome composition.

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Ciliopathy proteins interact with proteasomal components and regulate pr...
(A) Immunoblots show interaction between endogenous OFD1 and Flag-tagged RPT6 and endogenous BBS4 and GFP-tagged RPN10. An endogenous interaction was detected between BBS1 and RPN10 from protein lysate isolated from the testis of C57BL/6 mice. (B) Immunoblots show that suppression of OFD1 in HEK-293 cells reduced RPT2 protein levels in purified 26S proteasome. Densitometry measurements of proteasomal RPT2 protein levels were plotted (n = 3), and no significant difference in total RPT2 abundance was detected. Coomassie blue staining were carried out as a loading control and to measure the efficiency of the 26S proteasomal purification process. (C) Suppression of OFD1 in HEK-293 cells resulted in the reduction of pericentriolar RPN10 levels (normalized to cytoplasmic RPN10 levels) in OFD1-depleted cells. Scale bar: 10 μm. (D) HEK-293-FT cells transfected with pSuper control and pSuperOFD1 were subjected to sucrose gradient centrifugation. Fractions (fractions 6–12 of 13 fractions) were then analyzed by immunoblotting with antibodies against γ-tubulin and proteasomal subunits. In control cells, the fractions enriched with all proteasome subunits partially overlapped with fractions enriched with γ-tubulin (fraction 8), and when OFD1 was depleted, peak levels of RPN10, RPN13, RPT2, and RPT6 shifted significantly and resulted in a decrease in the overlap between γ-tubulin–enriched fractions and 19S subunit–enriched fractions. **P < 0.01; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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