Wei, Qing

AbstractServing as the cell's sensory antennae, primary cilia are linked to numerous human genetic diseases when they malfunction. DZIP1L, identified as one of the genetic causes of human autosomal recessive polycystic kidney disease (ARPKD), is an evolutionarily conserved ciliary basal body protein. Although it has been reported that DZIP1L is involved in the ciliary entry of PKD proteins, the underlying mechanism remains elusive. Here, an uncharacterized role of DZIP1L is reported in modulating the architecture and function of transition fibers (TFs), striking ciliary base structures essential for selective cilia gating. Using C. elegans as a model, C01G5.7 (hereafter termed DZIP‐1) is identified as the sole homolog of DZIP1L, which specifically localizes to TFs. While DZIP‐1 or ANKR‐26 (the ortholog of ANKRD26) deficiency shows subtle impact on TFs, co‐depletion of DZIP‐1 and ANKR‐26 disrupts TF assembly and cilia gating for soluble and membrane proteins, including the ortholog of ADPKD protein polycystin‐2. Notably, the synergistic role for DZIP1L and ANKRD26 in the formation and function of TFs is highly conserved in mammalian cilia. Hence, the findings illuminate an evolutionarily conserved role of DZIP1L in TFs architecture and function, highlighting TFs as a vital part of the ciliary gate implicated in ciliopathies ARPKD.

Abstract Cellular senescence contributes to tissue homeostasis and age-related pathologies. However, how senescence is initiated in damaged cells remains vague. Here, we discover that irreparable stresses induce transient biogenesis of cilia, which are used by stressed cells to directly communicate with the promyelocytic leukemia nuclear bodies (PML-NBs), the validated stress signaling hub, to initiate senescence responses. Mechanistically, a ciliary ARL13B-ARL3 GTPase cascade negatively regulates the association of transition fiber protein FBF1 and SUMO-conjugating enzyme UBC9. Irreparable stresses downregulate the ciliary ARLs to release UBC9, which SUMOylates FBF1 at the ciliary base. SUMOylated FBF1 then translocates to PML-NBs to promote PML-NB-dependent senescence initiation. Remarkably, Fbf1 suppression effectively subdues global senescence burden and prevents associated health-span decline in irradiation-treated mice. Collectively, our findings assign primary cilia a central role in inducing senescence program and identify them as promising targets to dampen senescence-associated detrimental damage in future senotherapy strategies.

Primary cilia serve as cellular antenna for various sensory signaling pathways. However, how the sensory receptors are properly targeted to the ciliary surface remains poorly understood. Here, we show that UBC-9, the sole E2 small ubiquitin-like modifier (SUMO)-conjugating enzyme, physically interacts with and SUMOylates the C terminus of small GTPase ARL-13, the worm orthologue of ARL13B that mutated in ciliopathy Joubert syndrome. Mutations that totally abolish the SUMOylation of ARL-13 do not affect its established role in ciliogenesis, but fail to regulate the proper ciliary targeting of various sensory receptors and consequently compromise the corresponding sensory functions. Conversely, constitutively SUMOylated ARL-13 fully rescues all ciliary defects of arl-13–null animals. Furthermore, SUMOylation modification of human ARL13B is required for the ciliary entry of polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease. Our data reveal a novel but conserved role for the SUMOylation modification of ciliary small GTPase ARL13B in specifically regulating the proper ciliary targeting of various sensory receptors.

Intraflagellar transport (IFT) machinery mediates the bidirectional movement of cargos that are required for the assembly and maintenance of cilia. However, little is known about how IFT is regulated in vivo. In this study, we show that the small guanosine triphosphatase (GTPase) adenosine diphosphate ribosylation factor–like protein 13 (ARL-13) encoded by the Caenorhabditis elegans homologue of the human Joubert syndrome causal gene ARL13B, localizes exclusively to the doublet segment of the cilium. arl-13 mutants have shortened cilia with various ultrastructural deformities and a disrupted association between IFT subcomplexes A and B. Intriguingly, depletion of ARL-3, another ciliary small GTPase, partially suppresses ciliogenesis defects in arl-13 mutants by indirectly restoring binding between IFT subcomplexes A and B. Rescue of arl-13 mutants by ARL-3 depletion is mediated by an HDAC6 deacetylase-dependent pathway. Thus, we propose that two conserved small GTPases, ARL-13 and ARL-3, coordinate to regulate IFT and that perturbing this balance results in cilia deformation.