The primary cilium controls programmed cell death via its proteasome-regulating function
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Abstract
Primary cilia are tiny cellular protrusions of nearly every vertebrate cell controlling multiple cellular processes, such as proliferation, differentiation, migration etc. Their dysfunction results in severe human diseases collectively referred to as ciliopathies. Remarkably, many ciliopathies are associated with increased programmed cell death (PCD). However, it is largely unknown how primary cilia regulate PCD. In in vitro (murine and human cells) and in vivo ( Xenopus laevis and mouse) models, we observed elevated PCD in the absence of the ciliopathy protein RPGRIP1L. Mechanistically, our data elucidated that RPGRIP1L controls PCD by governing the activity of the ciliary proteasome. By using super-resolution microscopy, we first showed that the apoptosis inducer MOAP1 localises to primary cilia. Furthermore, our investigations revealed that RPGRIP1L controls PCD via the degradation of MOAP1 by the ciliary proteasome. Based on our finding that two more ciliopathy proteins, TCTN1 and CEP290, modulate PCD via regulating the activity of the ciliary proteasome, we suggest that the proteasomal degradation of MOAP1 represents a general mechanism by which primary cilia control PCD.
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The treatment of serum-deprived wild-type NIH3T3 cells with MG132 resulted in an increased PCD (Fig. 3B) supporting our hypothesis. To test whether MG132 treatment affects PCD due to the inhibition of the ciliary proteasome or due to the inhibition of the overall cellular proteasomal activity, we treated serum-deprived Rpgrip1l-/-NIH3T3 cells with MG132. We found that the percentage of CC3-positive Rpgrip1l-/- NIH3T3 cells was not increased by the treatment with MG132
Curious what the ciliation levels are in MG132 treated serum starved cells in these experiments. There is a difference between ciliation percentage in the RPGRIP1l mutants vs wild type as in Figure 1C which also show a different percentage of CC3+ PCD in figure 1D but perhaps no difference in CC3+ PCD between the mutant and wild-type (RPGRIP1l +/+ w MG132 and RPGRIP1l …
The treatment of serum-deprived wild-type NIH3T3 cells with MG132 resulted in an increased PCD (Fig. 3B) supporting our hypothesis. To test whether MG132 treatment affects PCD due to the inhibition of the ciliary proteasome or due to the inhibition of the overall cellular proteasomal activity, we treated serum-deprived Rpgrip1l-/-NIH3T3 cells with MG132. We found that the percentage of CC3-positive Rpgrip1l-/- NIH3T3 cells was not increased by the treatment with MG132
Curious what the ciliation levels are in MG132 treated serum starved cells in these experiments. There is a difference between ciliation percentage in the RPGRIP1l mutants vs wild type as in Figure 1C which also show a different percentage of CC3+ PCD in figure 1D but perhaps no difference in CC3+ PCD between the mutant and wild-type (RPGRIP1l +/+ w MG132 and RPGRIP1l -/- w MG132) in the presence of MG132 (though these are not shown on the same graph and perhaps not done in the same experiment?)
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