A global analysis of IFT-A function reveals specialization for transport of membrane-associated proteins into cilia

Picariello, Tyler; Brown, Jason; Hou, Yuqing; Swank, Gregory; Cochran, Deborah A.; King, Oliver D.; Lechtreck, Karl‐Ferdinand; Pazour, Gregory J.; Witman, George B.

doi:10.1242/jcs.220749

Cited by 68 publications

(65 citation statements)

References 111 publications

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“…Since the IFT‐A complex mediates ciliary entry of membrane‐associated proteins, 6‐8 we next examined ciliary localization of ARL13B and INPP5E. While 100% of control, Thm2 ko, and triple allele mutant MEF showed the ciliary presence of ARL13B, approximately 90% of Thm1 ‐null and Thm1 ; Thm2 dko cilia were positive for ARL13B (Figures 6A,B and S4).…”

Section: Resultsmentioning

confidence: 99%

“…The IFT‐A complex, comprised of approximately 7 proteins, together with the dynein motor mediate retrograde transport, returning cargo from the tip to the base of the primary cilium. IFT‐A proteins also mediate ciliary entry of signaling and membrane‐associated proteins 6‐8 . Another protein complex, the BBSome, traffics signaling molecules to the cilium and throughout the cilium where it acts as an adaptor between the IFT complexes and the protein cargoes 9 .…”

Section: Introductionmentioning

confidence: 99%

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Genetic interaction of mammalian IFT‐A paralogs regulates cilia disassembly, ciliary entry of membrane protein, Hedgehog signaling, and embryogenesis

et al. 2020

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Primary cilia are sensory organelles that are essential for eukaryotic development and health. These antenna-like structures are synthesized by intraflagellar transport protein complexes, IFT-B and IFT-A, which mediate bidirectional protein trafficking along the ciliary axoneme. Here using mouse embryonic fibroblasts (MEF), we investigate the ciliary roles of two mammalian orthologues of Chlamydomonas IFT-A gene, IFT139, namely Thm1 (also known as Ttc21b) and Thm2 (Ttc21a). Thm1 loss causes perinatal lethality, and Thm2 loss allows survival into adulthood. At E14.5, the number of Thm1;Thm2 double mutant embryos is lower than that for a Mendelian ratio, indicating deletion of Thm1 and Thm2 causes mid-gestational lethality. We examined the ciliary phenotypes of mutant MEF. Thm1-mutant MEF show decreased cilia assembly, increased cilia disassembly, shortened primary cilia, a retrograde IFT defect for IFT and BBS proteins, and reduced ciliary entry of membrane-associated proteins. Thm1-mutant cilia also show a retrograde transport defect for the Hedgehog transducer, Smoothened, and an impaired response to Smoothened agonist, SAG. Thm2-null MEF show normal ciliary dynamics and Hedgehog signaling, but additional loss of a Thm1 allele impairs response to SAG. Further, Thm1;Thm2 doublemutant MEF show enhanced cilia disassembly, and increased impairment of INPP5E ciliary import. Thus, Thm1 and Thm2 have unique and redundant roles in MEF. Thm1 regulates cilia assembly, and alone and together with Thm2, regulates cilia disassembly, ciliary entry of membrane-associated protein, Hedgehog signaling, and embryogenesis. These findings shed light on mechanisms underlying Thm1-, Thm2or IFT-A-mediated ciliopathies. K E Y W O R D S development, mouse embryonic fibroblasts, mouse model, primary cilia 6370 | WANG et Al.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic interaction of mammalian IFT‐A paralogs regulates cilia disassembly, ciliary entry of membrane protein, Hedgehog signaling, and embryogenesis

et al. 2020

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“…The IFT-A complex, comprised of approximately 7 proteins, together with the dynein motor mediate retrograde transport, returning cargo from the tip to the base of the primary cilium. IFT-A proteins also mediate ciliary entry of signaling and membrane-associated proteins (6)(7)(8). Another protein complex, the BBSome, traffics signaling molecules to the cilium and throughout the cilium where it acts as an adaptor between the IFT complexes and the protein cargoes (9).…”

Section: Introductionmentioning

confidence: 99%

Genetic interaction of mammalian IFT-A paralogs regulates cilia disassembly, ciliary protein trafficking, Hedgehog signaling and embryogenesis

Wang

Allard

Pottorf

et al. 2019

Preprint

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Primary cilia are sensory organelles that are essential for eukaryotic development and health. These antenna-like structures are synthesized by intraflagellar transport protein complexes, IFT-B and IFT-A, which mediate bi-directional protein trafficking along the ciliary axoneme. Here using mouse embryonic fibroblasts (MEF), we investigate the ciliary roles of two mammalian orthologues of Chlamydomonas IFT-A gene, IFT139, namely Thm1 (also known as Ttc21b) and Thm2 (Ttc21a). Thm1 loss causes perinatal lethality, and Thm2 loss allows survival into adulthood. At E14.5, the number of Thm1;Thm2 double mutant embryos is lower than that for a Mendelian ratio, indicating deletion of Thm1 and Thm2 causes midgestational lethality. We examined the ciliary phenotypes of mutant MEF. Thm1-mutant MEF show decreased cilia assembly, shortened primary cilia, a retrograde IFT defect for IFT and BBS proteins, and reduced ciliary entry of membrane-associated proteins. Thm1-mutant cilia also show a retrograde transport defect for the Hedgehog transducer, Smoothened, and an impaired response to Smoothened agonist, SAG. Thm2-null MEF show normal ciliary dynamics and Hedgehog signaling, but additional loss of a Thm1 allele impairs response to SAG. Further, Thm1;Thm2 double mutant MEF show enhanced cilia disassembly, and relative to Thm1-null MEF, increased impairment of IFT81 retrograde transport and of INPP5E ciliary import. Thus, Thm1 and Thm2 have unique and redundant roles in MEF. Thm1 regulates cilia assembly, and together with Thm2, cilia disassembly. Moreover, Thm1 alone and together with Thm2, regulates ciliary protein trafficking, Hedgehog signaling, and embryogenesis. These findings shed light on mechanisms underlying Thm1-, Thm2-or IFT-A-mediated ciliopathies.

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“…Besides the subunits of the IFT-B complex, there is increasing evidence that IFT-A subunits are required for the transport of specific ciliary membrane proteins into or outside the cilium. A recently published article revealed that when truncated IFT140 lacking WD40 repeats was expressed in the null mutant, the axonemes of these cilia had a normal ultrastructure, but the composition of membrane and matrix were abnormal with a decrease in small GTPases, lipid-anchored proteins, and cell signaling proteins (Picariello et al, 2019), indicating that IFT-A subunits might also be specialized for importing the membraneassociated proteins.…”

Section: Discussionmentioning

confidence: 99%

Dissecting the Vesicular Trafficking Function of IFT Subunits

Yang

Huang

2020

Front. Cell Dev. Biol.

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Intraflagellar transport (IFT) was initially identified as a transport machine with multiple protein subunits, and it is essential for the assembly, disassembly, and maintenance of cilium/flagellum, which serves as the nexus of extracellular-to-intracellular signal integration. To date, in addition to its well-established and indispensable roles in ciliated cells, most IFT subunits have presented more general functions of vesicular trafficking in the non-ciliated cells. Thus, this review aims to summarize the recent progress on the vesicular trafficking functions of the IFT subunits and to highlight the issues that may arise in future research.

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A global analysis of IFT-A function reveals specialization for transport of membrane-associated proteins into cilia

Cited by 68 publications

References 111 publications

Genetic interaction of mammalian IFT‐A paralogs regulates cilia disassembly, ciliary entry of membrane protein, Hedgehog signaling, and embryogenesis

Genetic interaction of mammalian IFT‐A paralogs regulates cilia disassembly, ciliary entry of membrane protein, Hedgehog signaling, and embryogenesis

Genetic interaction of mammalian IFT-A paralogs regulates cilia disassembly, ciliary protein trafficking, Hedgehog signaling and embryogenesis

Dissecting the Vesicular Trafficking Function of IFT Subunits

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