A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened.

Seongjin Seo,Qihong Zhang,Kevin Bugge,Charles C Searby,David K Breslow,Maxence V Nachury,Val C Sheffield,Gregory S Barsh

doi:10.1371/journal.pgen.1002358

Abstract

Many signaling proteins including G protein-coupled receptors localize to primary cilia, regulating cellular processes including differentiation, proliferation, organogenesis, and tumorigenesis. Bardet-Biedl Syndrome (BBS) proteins are involved in maintaining ciliary function by mediating protein trafficking to the cilia. However, the mechanisms governing ciliary trafficking by BBS proteins are not well understood. Here, we show that a novel protein, Leucine-zipper transcription factor-like 1 (LZTFL1), interacts with a BBS protein complex known as the BBSome and regulates ciliary trafficking of this complex. We also show that all BBSome subunits and BBS3 (also known as ARL6) are required for BBSome ciliary entry and that reduction of LZTFL1 restores BBSome trafficking to cilia in BBS3 and BBS5 depleted cells. Finally, we found that BBS proteins and LZTFL1 regulate ciliary trafficking of hedgehog signal transducer, Smoothened. Our findings suggest that LZTFL1 is an important regulator of BBSome ciliary trafficking and hedgehog signaling.

Highlights

Primary cilia are microtubule-based subcellular organelles projecting from the surface of cells
Among the known Bardet-Biedl Syndrome (BBS) proteins, seven form a complex, the BBSome, which was recently defined as a coat complex transporting membrane proteins between plasma and ciliary membranes
We determined that LZTLF1 negatively regulates BBSome ciliary trafficking and that reduction of Leucine-zipper transcription factor-like 1 (LZTFL1) activity can compensate for loss of certain BBS proteins and restores BBSome ciliary trafficking

Summary

Introduction

Primary cilia are microtubule-based subcellular organelles projecting from the surface of cells. Loss of cilia or ciliary dysfunction has been linked to a series of related genetic disorders in humans [3,4]. These disorders, collectively termed ciliopathies, share common features such as cystic kidney disease, retinal degeneration, and polydactyly. Among the known BBS proteins, seven proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9) and BBIP10 form a stable complex, the BBSome, which mediates protein trafficking to the ciliary membrane [9,10,11]. Three BBS proteins (BBS6, BBS10, BBS12) form another complex with the CCT/TRiC family of group II chaperonins and mediate BBSome assembly [8]

Methods

Discussion

Conclusion