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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 1

Accumulation of GFP in Bbs4–/– mice.

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Accumulation of GFP in Bbs4–/– mice.
 
(A and B) Immunoblotting with ant...
(A and B) Immunoblotting with anti-GFP to examine the kidney (P80), liver (P144), several brain components (P80), and retina (P12–P126) (B) of UbG76V-Gfp Bbs4–/– mice, with UbG76V-Gfp WT littermates used as controls. Samples in each panel for the brain were run on the same gel but were noncontiguous. (C) Immunohistochemistry of retinal sections of P23 and P126 UbG76V-Gfp transgenic mice. Progressive retinal degeneration and GFP accumulation in photoreceptors (OS and IS, and ONL) were observed in Bbs4–/– mice, but not in WT littermates. OS was immunolabeled with anti–s-opsin; ONL and INL were labeled with DAPI staining. RPE, retinal pigment epithelium; OS, outer segment of the photoreceptors; IS, inner segment; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. White boxes delimit the enlarged images, showing OS and IS. HP, hippocampus; CX, cortex; CB, cerebellum. White boxes delimit the enlarged images, showing OS and IS. Scale bar: 25 μm in images and inserts. Bar graphs showing standard error of the mean are plotted adjacent to each blot. *P < 0.05; **P < 0.01.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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