Abstract
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.
Highlights
Cilia are slender subcellular structures that protrude from the surfaces of most eukaryotic cell types, where they carry out functions associated with sensation and/or motility
Concluding Remarks Human MIP-T3 (Microtubule-interacting protein associated with TRAF3), termed TRAF3IP1 (TNF Receptor-Associated Factor 3 Interacting Protein 1), is a poorly-characterized protein previously implicated in TRAF3 function and shown to bind microtubules [66]
Given that MIP-T3 protein orthologs are present in organisms lacking both TRAF3 and DISC1, including B. dendrobatidis, Chlamydomonas and C. elegans (Figure 1A), we hypothesized that MIP-T3 likely performs a more general, evolutionarily conserved function—one related to cilia formation [21]
Summary
Cilia are slender subcellular structures that protrude from the surfaces of most eukaryotic cell types, where they carry out functions associated with sensation and/or motility. Nonmotile (primary) cilia are nearly ubiquitous in multicellular organisms, and perform a wide range of sensory functions, including chemosensation/olfaction, photoreception, and mechanosensation [1,2,3,4,5]. Cilia are organelles that require several hundred proteins to support their motility and/or sensory and signaling functions [21,22]. The IFT particles, first observed in Chlamydomonas [26] consist of anterograde Kinesin-2 motor(s) that move cargo into the cilia and a retrograde dynein motor involved in recycling components back to the base (basal body). The cilia of C. elegans are non-motile and restricted
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