Hedgehog-induced Ciliary Trafficking of Kinesin-4 Motor KIF7 Requires Intraflagellar Transport but Not KIF7's Microtubule Binding

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2021 Oct 27

PMID 34705483

Citations 5

Authors

Yang Yue

Martin F Engelke

T Lynne Blasius

Kristen J Verhey

Affiliations

Soon will be listed here.

Abstract

The kinesin-4 motor KIF7 is a conserved regulator of the Hedgehog signaling pathway. In vertebrates, Hedgehog signaling requires the primary cilium, and KIF7 and Gli transcription factors accumulate at the cilium tip in response to Hedgehog activation. Unlike conventional kinesins, KIF7 is an immotile kinesin and its mechanism of ciliary accumulation is unknown. We generated KIF7 variants with altered microtubule binding or motility. We demonstrate that microtubule binding of KIF7 is not required for the increase in KIF7 or Gli localization at the cilium tip in response to Hedgehog signaling. In addition, we show that the immotile behavior of KIF7 is required to prevent ciliary localization of Gli transcription factors in the absence of Hedgehog signaling. Using an engineered kinesin-2 motor that enables acute inhibition of intraflagellar transport, we demonstrate that kinesin-2 KIF3A/KIF3B/KAP mediates the translocation of KIF7 to the cilium tip in response to Hedgehog pathway activation. Together, these results suggest that KIF7's role at the tip of the cilium is unrelated to its ability to bind to microtubules.

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References

Yue Y, Blasius T, Zhang S, Jariwala S, Walker B, Grant B . Altered chemomechanical coupling causes impaired motility of the kinesin-4 motors KIF27 and KIF7. J Cell Biol. 2018; 217(4):1319-1334. PMC: 5881503. DOI: 10.1083/jcb.201708179. View

Jiang S, Mani N, Wilson-Kubalek E, Ku P, Milligan R, Subramanian R . Interplay between the Kinesin and Tubulin Mechanochemical Cycles Underlies Microtubule Tip Tracking by the Non-motile Ciliary Kinesin Kif7. Dev Cell. 2019; 49(5):711-730.e8. PMC: 6550315. DOI: 10.1016/j.devcel.2019.04.001. View

Nakata T, Hirokawa N . Point mutation of adenosine triphosphate-binding motif generated rigor kinesin that selectively blocks anterograde lysosome membrane transport. J Cell Biol. 1995; 131(4):1039-53. PMC: 2200001. DOI: 10.1083/jcb.131.4.1039. View

Cochran J . Kinesin Motor Enzymology: Chemistry, Structure, and Physics of Nanoscale Molecular Machines. Biophys Rev. 2017; 7(3):269-299. PMC: 5418420. DOI: 10.1007/s12551-014-0150-6. View

Qi X, Li X . Mechanistic Insights into the Generation and Transduction of Hedgehog Signaling. Trends Biochem Sci. 2020; 45(5):397-410. PMC: 7174405. DOI: 10.1016/j.tibs.2020.01.006. View

Liu Y, Couzens A, Deshwar A, B McBroom-Cerajewski L, Zhang X, Puviindran V . The PPFIA1-PP2A protein complex promotes trafficking of Kif7 to the ciliary tip and Hedgehog signaling. Sci Signal. 2014; 7(355):ra117. DOI: 10.1126/scisignal.2005608. View

Cheng L, Desai J, Miranda C, Duncan J, Qiu W, Nugent A . Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling. Neuron. 2014; 82(2):334-49. PMC: 4002761. DOI: 10.1016/j.neuron.2014.02.038. View

Webb S, Mukhopadhyay A, Roberts A . Intraflagellar transport trains and motors: Insights from structure. Semin Cell Dev Biol. 2020; 107:82-90. PMC: 7561706. DOI: 10.1016/j.semcdb.2020.05.021. View

Bangs F, Anderson K . Primary Cilia and Mammalian Hedgehog Signaling. Cold Spring Harb Perspect Biol. 2016; 9(5). PMC: 5411695. DOI: 10.1101/cshperspect.a028175. View

10.

Ishiguro K, Watanabe O, Nakamura M, Yamamura T, Matsushita M, Goto H . Combinational use of lipid-based reagents for efficient transfection of primary fibroblasts and hepatoblasts. Biotechniques. 2017; 63(1):37-39. DOI: 10.2144/000114569. View

11.

Pan J, Snell W . Chlamydomonas shortens its flagella by activating axonemal disassembly, stimulating IFT particle trafficking, and blocking anterograde cargo loading. Dev Cell. 2005; 9(3):431-8. DOI: 10.1016/j.devcel.2005.07.010. View

12.

He M, Agbu S, Anderson K . Microtubule Motors Drive Hedgehog Signaling in Primary Cilia. Trends Cell Biol. 2016; 27(2):110-125. PMC: 5258846. DOI: 10.1016/j.tcb.2016.09.010. View

13.

Crevel I, Lockhart A, Cross R . Weak and strong states of kinesin and ncd. J Mol Biol. 1996; 257(1):66-76. DOI: 10.1006/jmbi.1996.0147. View

14.

Carpenter B, Barry R, Verhey K, Allen B . The heterotrimeric kinesin-2 complex interacts with and regulates GLI protein function. J Cell Sci. 2015; 128(5):1034-50. PMC: 4342584. DOI: 10.1242/jcs.162552. View

15.

Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen J, Phamluong K . The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol. 2009; 19(15):1320-6. DOI: 10.1016/j.cub.2009.06.046. View

16.

Craft J, Harris J, Hyman S, Kner P, Lechtreck K . Tubulin transport by IFT is upregulated during ciliary growth by a cilium-autonomous mechanism. J Cell Biol. 2015; 208(2):223-37. PMC: 4298693. DOI: 10.1083/jcb.201409036. View

17.

Zeng H, Jia J, Liu A . Coordinated translocation of mammalian Gli proteins and suppressor of fused to the primary cilium. PLoS One. 2011; 5(12):e15900. PMC: 3012114. DOI: 10.1371/journal.pone.0015900. View

18.

Prevo B, Scholey J, Peterman E . Intraflagellar transport: mechanisms of motor action, cooperation, and cargo delivery. FEBS J. 2017; 284(18):2905-2931. PMC: 5603355. DOI: 10.1111/febs.14068. View

19.

Liem Jr K, He M, Ocbina P, Anderson K . Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proc Natl Acad Sci U S A. 2009; 106(32):13377-82. PMC: 2726420. DOI: 10.1073/pnas.0906944106. View

20.

Woehlke G, Ruby A, Hart C, Ly B, Vale R . Microtubule interaction site of the kinesin motor. Cell. 1997; 90(2):207-16. DOI: 10.1016/s0092-8674(00)80329-3. View