Abstract
Cilia, which either generate coordinated motion or sense environmental cues and transmit corresponding signals to the cell body, are highly conserved hair-like structures that protrude from the cell surface among diverse species. Disruption of ciliary functions leads to numerous human disorders, collectively referred to as ciliopathies. Cilia are mechanically supported by axonemes, which are composed of microtubule doublets. It has been recognized for several decades that tubulins in axonemes undergo glutamylation, a post-translational polymodification, that conjugates glutamic acid chains onto the C-terminal tail of tubulins. However, the physiological roles of axonemal glutamylation were not uncovered until recently. This review will focus on how cells modulate glutamylation on ciliary axonemes and how axonemal glutamylation regulates cilia architecture and functions, as well as its physiological importance in human health. We will also discuss the conventional and emerging new strategies used to manipulate glutamylation in cilia.
Highlights
Specialty section: This article was submitted to Cell Adhesion and Migration, a section of the journal Frontiers in Cell and Developmental
Primary cilium acts as a central hub for a wide spectrum of signaling pathways required for embryonic development and tissue homeostasis, such as hedgehog (Hh), canonical and non-canonical Wingless (WNT), transforming growth factorβ (TGF-β), platelet-derived growth factor receptor (PDGFR), and various G protein-coupled receptor (GPCR) signalings (Goetz and Anderson, 2010; Nishimura et al, 2019)
During ciliogenesis in human retinal pigment epithelium (RPE) cells, ARL13B (ADP-ribosylation factor-like protein 13B) and RAB11/FIP5 (RAB11 family interacting protein1)-positive vesicles coordinately promote the transport of TTLL5- and TTLL6-containing vesicles to the ciliary base, which results in an increase in general polyglutamylation with long side chains in the cilia (He et al, 2018)
Summary
The cilium is a hair-like organelle ubiquitously found on the surface of eukaryotic cells, each of which has a core formed by a microtubule-based axoneme and a basal body (transformed from the mother centriole) that anchors the cilium (Figure 1). Other than the central pair of microtubule doublets, motile cilia possess unique structures such as dynein arms, radial spokes, and nexin-dynein regulatory complex (N-DRC), which attach to outer doublets and act together to produce ATP-driven beating or waving motion of motile cilia. With this kinetic capability, motile cilia can propel the movement of the ciliated cells/organisms, or generate fluid flow on the surface of the ciliated cells. Despite the importance of cilia in both cell biology and human health, many central questions in the context of cilia, especially primary cilia; including how cilia in different cell types are modified to execute sensory functions, how cilia signalings convert into specific cellular behaviors, and most importantly, the molecular function of most identified ciliopathy proteins, remain poorly understood
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