Trypanosome IFT mutants provide insight into the motor location for mobility of the flagella connector and flagellar membrane formation

Davidge, Jacqueline; Chambers, Emma L.; Dickinson, Harriet; Towers, Katie; Ginger, Michael L.; McKean, Paul G.; Gull, Keith

doi:10.1242/jcs.03203

Cited by 91 publications

(127 citation statements)

References 31 publications

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“…Instead, an axonemeless membrane sleeve extended alongside the cell body from TZ stubs (Fig. 6 C and D), similar to that observed in anterograde IFT mutants (40,41).…”

Section: Tz and Ciliary Subdomains Defined By Protein Localization Usingsupporting

confidence: 76%

Cilium transition zone proteome reveals compartmentalization and differential dynamics of ciliopathy complexes

Dean

Moreira-Leite

Varga

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The transition zone (TZ) of eukaryotic cilia and flagella is a structural intermediate between the basal body and the axoneme that regulates ciliary traffic. Mutations in genes encoding TZ proteins (TZPs) cause human inherited diseases (ciliopathies). Here, we use the trypanosome to identify TZ components and localize them to TZ subdomains, showing that the Bardet-Biedl syndrome complex (BBSome) is more distal in the TZ than the Meckel syndrome (MKS) complex. Several of the TZPs identified here have human orthologs. Functional analysis shows essential roles for TZPs in motility, in building the axoneme central pair apparatus and in flagellum biogenesis. Analysis using RNAi and HaloTag fusion protein approaches reveals that most TZPs (including the MKS ciliopathy complex) show long-term stable association with the TZ, whereas the BBSome is dynamic. We propose that some Bardet-Biedl syndrome and MKS pleiotropy may be caused by mutations that impact TZP complex dynamics.transition zone | cilium/flagellum | BBSome | MKS/B9 complex | trypanosome C ilia, or flagella (the two terms are used here interchangeably), are multifunctional organelles that were present in the last common eukaryotic ancestor (1). Defects in cilia are responsible for pleiotropic human diseases (called ciliopathies) and their function is essential for pathogenesis in protozoan parasites (2, 3).During ciliogenesis, a microtubule organizing center called the "basal body" docks at the membrane. Basal bodies are built from nine microtubule triplets and two microtubules from each triplet extend to form a transition zone (TZ) and, ultimately, the axoneme. Thus, the TZ represents a structural junction between the basal body and the axoneme.As expected from its strategic position between the basal body and the axoneme, the TZ acts as a "ciliary gate" that controls ciliary composition and function (4). Many ciliopathies are caused by defects in complexes that associate with the TZ, including Meckel syndrome (MKS), Joubert syndrome and Bardet-Biedl syndrome (BBS). Studies using murine kidney epithelial cells and embryos suggest that the MKS complex demarcates the ciliary membrane by forming a diffusion barrier at the base of the cilium (5-7). On the other hand, the BBS complex (BBSome) is an adapter for intraflagellar transport (IFT) complexes that cross the TZ barrier to transport sensory proteins between the ciliary membrane and the cell body (8, 9).The TZ has distinctive structural features. At the proximal boundary of the TZ, where the basal body C tubule terminates, a "terminal plate" crosses the TZ. Studies in Tetrahymena suggest that the terminal plate contains pores for the passage of IFT "trains" that deliver axonemal components to the distal tip of flagella (10). Striated transitional fibers radiate from the distal end of the basal body triplets to join the plasma membrane (11-14), forming blades thought to create a physical barrier preventing vesicles from entering the ciliary lumen. Electron microscopy (EM) studies in Chlamydomonas suggest that...

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“…Instead, an axonemeless membrane sleeve extended alongside the cell body from TZ stubs (Fig. 6 C and D), similar to that observed in anterograde IFT mutants (40,41).…”

Section: Tz and Ciliary Subdomains Defined By Protein Localization Usingsupporting

confidence: 76%

Cilium transition zone proteome reveals compartmentalization and differential dynamics of ciliopathy complexes

Dean

Moreira-Leite

Varga

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Assembly of the T. brucei flagellum has been shown to be dependent on the conserved process of IFT (Rosenbaum, 2002;Kohl et al, 2003;Davidge et al, 2006). In this process, axoneme precursors are transported to the distal tip of the flagellum via IFT particles whose movement is powered by heterotrimeric kinesin (Kozminski et al, 1995).…”

Section: Flagellum Biogenesismentioning

confidence: 99%

The flagellum of Trypanosoma brucei: New tricks from an old dog

Ralston

Hill

2008

International Journal for Parasitology

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African trypanosomes, i.e. Trypanosoma brucei and related sub-species, are devastating human and animal pathogens that cause significant human mortality and limit sustained economic development in sub-Saharan Africa. Trypanosoma brucei is a highly motile protozoan parasite and coordinated motility is central to both disease pathogenesis in the mammalian host and parasite development in the tsetse fly vector. Since motility is critical for parasite development and pathogenesis, understanding unique aspects of the T. brucei flagellum may uncover novel targets for therapeutic intervention in African sleeping sickness. Moreover, studies of conserved features of the T. brucei flagellum are directly relevant to understanding fundamental aspects of flagellum and cilium function in other eukaryotes, making T. brucei an important model system. The T. brucei flagellum contains a canonical 9 + 2 axoneme, together with additional features that are unique to kinetoplastids and a few closely-related organisms. Until recently, much of our knowledge of the structure and function of the trypanosome flagellum was based on analogy and inference from other organisms. There has been an explosion in functional studies in T. brucei in recent years, revealing conserved as well as novel and unexpected structural and functional features of the flagellum. Most notably, the flagellum has been found to be an essential organelle, with critical roles in parasite motility, morphogenesis, cell division and immune evasion. This review highlights recent discoveries on the T. brucei flagellum.

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“…The FC then provides constant attachment of the extending new flagellum tip on the old flagellum while migrating along the old flagellum (14,15). This migration is independent of new axoneme elongation (12,16). The FC movement ceases when the structure reaches a "stop point" (16).…”

mentioning

confidence: 99%

“…This migration is independent of new axoneme elongation (12,16). The FC movement ceases when the structure reaches a "stop point" (16). Continued extension of the new flagellum is thus associated with a posterior migration of the new basal body, together with the associated kinetoplast (mitochondrial DNA), contributing to mitochondrial genome segregation (16).…”

mentioning

confidence: 99%

“…The FC movement ceases when the structure reaches a "stop point" (16). Continued extension of the new flagellum is thus associated with a posterior migration of the new basal body, together with the associated kinetoplast (mitochondrial DNA), contributing to mitochondrial genome segregation (16). This robust flagella connection is severed by an unknown mechanism during the late stage of cytokinesis (15).…”

mentioning

confidence: 99%

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Protein diversity in discrete structures at the distal tip of the trypanosome flagellum

Varga

Moreira-Leite

Portman

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The distal end of the eukaryotic flagellum/cilium is important for axonemal growth and signaling and has distinct biomechanical properties. Specific flagellum tip structures exist, yet their composition, dynamics, and functions are largely unknown. We used biochemical approaches to identify seven constituents of the flagella connector at the tip of an assembling trypanosome flagellum and three constituents of the axonemal capping structure at the tips of both assembling and mature flagella. Both tip structures contain evolutionarily conserved as well as kinetoplastid-specific proteins, and component assembly into the structures occurs very early during flagellum extension. Localization and functional studies reveal that the flagella connector membrane junction is attached to the tips of extending microtubules of the assembling flagellum by a kinesin-15 family member. On the opposite side, a kinetoplastid-specific kinesin facilitates attachment of the junction to the microtubules in the mature flagellum. Functional studies also suggest roles of several other components and the definition of subdomains in the tip structures.

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Trypanosome IFT mutants provide insight into the motor location for mobility of the flagella connector and flagellar membrane formation

Cited by 91 publications

References 31 publications

Cilium transition zone proteome reveals compartmentalization and differential dynamics of ciliopathy complexes

Cilium transition zone proteome reveals compartmentalization and differential dynamics of ciliopathy complexes

The flagellum of Trypanosoma brucei: New tricks from an old dog

Protein diversity in discrete structures at the distal tip of the trypanosome flagellum

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