A conserved mechanism for the retrieval of polyubiquitinated proteins from cilia
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (Arcadia Science)
Abstract
The temporospatial distribution of proteins within cilia is regulated by intraflagellar transport (IFT), wherein molecular trains shuttle between the cell body and cilium. Defects in this process impair various signal-transduction pathways and cause ciliopathies. Although K63-linked ubiquitination appears to trigger protein export from cilia, the mechanisms coupling polyubiquitinated proteins to IFT remain unclear. Using a multidisciplinary approach, we demonstrate that a complex of CFAP36, a conserved ciliary protein of previously unknown function, and ARL3, a GTPase involved in ciliary import, binds polyubiquitinated proteins and links them to retrograde IFT trains. CFAP36 uses a coincidence detection mechanism to simultaneously bind two IFT subunits accessible only in retrograde trains. Depleting CFAP36 accumulates K63-linked ubiquitin in cilia and disrupts Hedgehog signaling, a pathway reliant on the retrieval of ubiquitinated receptors. These findings advance our understanding of ubiquitin-mediated protein transport and ciliary homeostasis, and demonstrate how structural changes in IFT trains achieve cargo selectivity.
Article activity feed
-
CFAP36 has broad ubiquitin-dependent specificity for membrane-associated proteins
Do you see excess membrane budding/blebbing/ectocytosis in CFAP ubiquitin-binding mutants that can't retrieve membrane-associated cargo like in BBSome mutants?
-
TIRF microscopy analyses of these three strains revealed that while the mutations did not prevent CFAP36 from entering flagella, they inhibited its movement within the flagellum.
Curious if you're actually in TIRF with this much cell body fluorescence and if you have WT CFAP36 data from this same experiment?
-
We discounted USP5 as an IFT adaptor because of its well-characterized function as a deubiquitinase
Since deubiquitinases can be regulated, can function non-catalytically, and have specificity for ubiquitinated substrates, perhaps USP5 could still be a viable candidate
-
