Abstract

Understanding how the nucleoskeleton is optimized for efficient transcription factor navigation through the nucleus remains critical for developing targeted therapeutics. The GLI1 transcription factor must maintain maximal Hedgehog pathway output in basal cell carcinomas (BCCs), and we have previously shown that resistant BCCs increase GLI1 deacetylation through atypical protein kinase C?/? (aPKC) and HDAC1. Here we identify a lamina-associated polypeptide 2 (LAP2) isoform-dependent nuclear chaperoning system that regulates GLI1 movement between the nuclear lamina and nucleoplasm to achieve maximal activation. LAP2? forms a two-site interaction with the GLI1 zinc-finger domain and acetylation site, stabilizing an acetylation-dependent reserve on the inner nuclear membrane (INM). By contrast, the nucleoplasmic LAP2? competes with LAP2? for GLI1 while scaffolding HDAC1 to deacetylate the secondary binding site. aPKC functions to promote GLI1 association with LAP2? by nucleoskeletal patterning, promoting egress off the INM. Disruption of this shuttling mechanism in patient BCCs results in significant depletion of hedgehog signaling output. Investigations into functional markers of LAP2 chaperon patterning may prove to be useful in developing diagnostic strategies for targeted BCC therapeutics. GLI1 intranuclear trafficking by LAP2 isoforms represents a powerful signal amplifier in BCCs with implications for zinc finger-based signal transduction, diagnostics, and therapeutics.

Financial Disclosure:
No current or relevant financial relationships exist.