Ling, Kun

HYLS1 regulates the ciliary phosphoinositide and hedgehog pathways, implicating a novel pathogenic mechanism for HLS syndrome.

The mechanisms underlying E‐cadherin clustering and AJ maturation are not fully understood although the E‐cadherin‐mediated formation of adherens junctions (AJs) is essential for the morphogenesis of epithelial cells. Here we report that the association between type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) and Exo70 regulated the transport and clustering of Ecadherin on the plasma membrane and, subsequently, the extension of nascent E‐cadherin adhesions. We also observed that PI4,5P(2) accumulation at E‐cadherin clusters during the assembly of E‐cadherin adhesions. PIPKIγ‐generated PI4,5P(2) is required for recruiting Exo70 to newly formed E‐cadherin junctions and facilitates the assembly and maturation of AJs. Additionally, Rho activity and actin structure were impaired by loss of Exo70 and/or PIPKIγ. These results support a model in which PIPKIγ and PIPKIγ‐generated PI4,5P(2) pools at nascent E‐cadherin contacts cue Exo70 targeting and orients the tethering of exocyst‐associated E‐cadherin. This could be an important mechanism that regulates E‐cadherin clustering and AJ maturation, and actin reorganization, which is essential for the establishment of solid, polarized epithelial structures.

Although the immune checkpoint role of programmed death ligand 1 (PD-L1) has been established and targeted in cancer immunotherapy, the tumor-intrinsic role of PD-L1 is less appreciated in tumor biology and therapeutics development, partly because of the incomplete mechanistic understanding. Here we demonstrate a potentially novel mechanism by which PD-L1 promotes the epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) cells by suppressing the destruction of the EMT transcription factor Snail. PD-L1 directly binds to and inhibits the tyrosine phosphatase PTP1B, thus preserving p38-MAPK activity that phosphorylates and inhibits glycogen synthase kinase 3β (GSK3β). Via this mechanism, PD-L1 prevents the GSK3β-mediated phosphorylation, ubiquitination, and degradation of Snail and consequently promotes the EMT and metastatic potential of TNBC. Significantly, PD-L1 antibodies that confine the tumor-intrinsic PD-L1/Snail pathway restricted TNBC progression in immunodeficient mice. More importantly, targeting both tumor-intrinsic and tumor-extrinsic functions of PD-L1 showed strong synergistic tumor suppression effect in an immunocompetent TNBC mouse model. Our findings support that PD-L1 intrinsically facilitates TNBC progression by promoting the EMT, and this potentially novel PD-L1 signaling pathway could be targeted for better clinical management of PD-L1–overexpressing TNBCs.

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.