An essential role for DYF-11/MIP-T3 in assembling functional intraflagellar transport complexes.
MIP-T3 is a human protein found previously to associate with microtubules and the kinesin-interacting neuronal protein DISC1 (Disrupted-in-Schizophrenia 1), but whose cellular function(s) remains unknown. Here we demonstrate that the C. elegans MIP-T3 ortholog DYF-11 is an intraflagellar transport (IFT) protein that plays a critical role in assembling functional kinesin motor-IFT particle complexes. We have cloned a loss of function dyf-11 mutant in which several key components of the IFT machinery, including Kinesin-II, as well as IFT subcomplex A and B proteins, fail to enter ciliary axonemes and/or mislocalize, resulting in compromised ciliary structures and sensory functions, and abnormal lipid accumulation. Analyses in different mutant backgrounds further suggest that DYF-11 functions as a novel component of IFT subcomplex B. Consistent with an evolutionarily conserved cilia-associated role, mammalian MIP-T3 localizes to basal bodies and cilia, and zebrafish mipt3 functions synergistically with the Bardet-Biedl syndrome protein Bbs4 to ensure proper gastrulation, a key cilium- and basal body-dependent developmental process. Our findings therefore implicate MIP-T3 in a previously unknown but critical role in cilium biogenesis and further highlight the emerging role of this organelle in vertebrate development.
Li
Chunmei
C
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Inglis
Peter N
PN
Leitch
Carmen C
CC
Efimenko
Evgeni
E
Zaghloul
Norann A
NA
Mok
Calvin A
CA
Davis
Erica E
EE
Bialas
Nathan J
NJ
Healey
Michael P
MP
Héon
Elise
E
Zhen
Mei
M
Swoboda
Peter
P
Katsanis
Nicholas
N
Leroux
Michel R
MR
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D001693:Biological Transport, Active; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002923:Cilia / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D018509:DNA, Helminth / Q000235:genetics; D005407:Flagella / Q000502:physiology*; D017238:Genes, Helminth; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D009024:Morphogenesis; D046912:Multiprotein Complexes; D009154:Mutation; D009475:Neurons, Afferent / Q000502:physiology; D010641:Phenotype; D015398:Signal Transduction
D029742:Caenorhabditis elegans Proteins; D017931:DNA Primers; D018509:DNA, Helminth; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; C412724:TRAF3IP1 protein, human