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J Cell Sci. 2014 Nov 1;127(Pt 21):4714-27. doi: 10.1242/jcs.155275. Epub 2014 Aug 22.

NPHP4 controls ciliary trafficking of membrane proteins and large soluble proteins at the transition zone.

Author information

1
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
3
Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA.
5
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
6
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA George.Witman@umassmed.edu.

Abstract

The protein nephrocystin-4 (NPHP4) is widespread in ciliated organisms, and defects in NPHP4 cause nephronophthisis and blindness in humans. To learn more about the function of NPHP4, we have studied it in Chlamydomonas reinhardtii. NPHP4 is stably incorporated into the distal part of the flagellar transition zone, close to the membrane and distal to CEP290, another transition zone protein. Therefore, these two proteins, which are incorporated into the transition zone independently of each other, define different domains of the transition zone. An nphp4-null mutant forms flagella with nearly normal length, ultrastructure and intraflagellar transport. When fractions from isolated wild-type and nphp4 flagella were compared, few differences were observed between the axonemes, but the amounts of certain membrane proteins were greatly reduced in the mutant flagella, and cellular housekeeping proteins >50 kDa were no longer excluded from mutant flagella. Therefore, NPHP4 functions at the transition zone as an essential part of a barrier that regulates both membrane and soluble protein composition of flagella. The phenotypic consequences of NPHP4 mutations in humans likely follow from protein mislocalization due to defects in the transition zone barrier.

KEYWORDS:

CEP290; Chlamydomonas; Cilia; Flagella; Nephrocystin-4; Transition zone

PMID:
25150219
PMCID:
PMC4215714
DOI:
10.1242/jcs.155275
[Indexed for MEDLINE]
Free PMC Article

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