RT Journal Article
SR Electronic
T1 Multiple Ciliary Localization Signals Control INPP5E Ciliary Targeting
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.25.477585
DO 10.1101/2022.01.25.477585
A1 Dario Cilleros-Rodriguez
A1 Raquel Martin-Morales
A1 Pablo Barbeito
A1 Abhijit Deb Roy
A1 Abdelhalim Loukil
A1 Belen Sierra-Rodero
A1 Gonzalo Herranz
A1 Olatz Pampliega
A1 Modesto Redrejo-Rodriguez
A1 Sarah C. Goetz
A1 Manuel Izquierdo
A1 Takanari Inoue
A1 Francesc R. Garcia-Gonzalo
YR 2022
UL http://biorxiv.org/content/early/2022/01/26/2022.01.25.477585.abstract
AB Primary cilia are sensory membrane protrusions whose dysfunction causes diseases named ciliopathies. INPP5E is a ciliary phosphoinositide phosphatase mutated in ciliopathies like Joubert syndrome. INPP5E regulates numerous ciliary functions, such as cilium stability, trafficking, signaling, or exovesicle release. Despite its key ciliary roles, how INPP5E accumulates in cilia remains poorly understood. Herein, we show that INPP5E ciliary targeting requires its folded catalytic domain and is controlled by four ciliary localization signals (CLSs), the first two of which we newly discover: LLxPIR motif (CLS1), W383 (CLS2), FDRxLYL motif (CLS3) and CaaX box (CLS4). We answer two long-standing questions in the field. First, partial redundancy between CLS1 and CLS4 explains why CLS4 is dispensable for ciliary targeting. Second, the essential need for CLS2 on the catalytic domain surface clarifies why CLS3 and CLS4 are together insufficient for ciliary accumulation. Furthermore, we reveal that some Joubert syndrome mutations in INPP5E catalytic domain affect its ciliary targeting, and shed light on the mechanisms of action of each CLS. Thus, we find that CLS2 and CLS3 promote interaction with TULP3 and ARL13B, while downregulating CEP164 binding. On the other hand, CLS4 recruits PDE6D, RPGR and ARL13B, and cooperates with CLS1 in ATG16L1 binding. Lastly, we show INPP5E immune synapse targeting is CLS-independent. Altogether, we reveal unusual complexity in INPP5E ciliary targeting mechanisms, likely reflecting its multiple key roles in ciliary biology.Competing Interest StatementThe authors have declared no competing interest.