N-terminal dual lipidation-coupled molecular targeting into the primary cilium

Masahiro Kumeta; Yulia Panina; Hiroya Yamazaki; Kunio Takeyasu; Shige H Yoshimura

doi:10.1111/gtc.12603

N-terminal dual lipidation-coupled molecular targeting into the primary cilium

Genes Cells. 2018 Jun 13. doi: 10.1111/gtc.12603. Online ahead of print.

Authors

Masahiro Kumeta¹, Yulia Panina^{1

2}, Hiroya Yamazaki¹, Kunio Takeyasu^{1

3}, Shige H Yoshimura¹

Affiliations

¹ Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
² Quantitative Biology Center (QBiC), Osaka, Japan.
³ Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.

PMID: 29900630
DOI: 10.1111/gtc.12603

Abstract

The primary cilium functions as an "antenna" for cell signaling, studded with characteristic transmembrane receptors and soluble protein factors, raised above the cell surface. In contrast to the transmembrane proteins, targeting mechanisms of nontransmembrane ciliary proteins are poorly understood. We focused on a pathogenic mutation that abolishes ciliary localization of retinitis pigmentosa 2 protein and revealed a dual acylation-dependent ciliary targeting pathway. Short N-terminal sequences which contain myristoylation and palmitoylation sites are sufficient to target a marker protein into the cilium in a palmitoylation-dependent manner. A Golgi-localized palmitoyltransferase DHHC-21 was identified as the key enzyme controlling this targeting pathway. Rapid turnover of the targeted protein was ensured by cholesterol-dependent membrane fluidity, which balances highly and less-mobile populations of the molecules within the cilium. This targeting signal was found in a set of signal transduction molecules, suggesting a general role of this pathway in proper ciliary organization, and dysfunction in ciliary disorders.

Keywords: DHHC-21; molecular targeting; molecular transport; myristoylation; palmitoylation; primary cilium.