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REVIEWS The tubulin code and its role in controlling microtubule properties and functions Carsten Janke 1,2 ✉ and Maria M. Magiera 1,2 ✉ Abstract | Microtubules are core components of the eukaryotic cytoskeleton with essential roles in cell division, shaping, motility and intracellular transport. Despite their functional heterogeneity , microtubules have a highly conserved structure made from almost identical molecular building blocks: the tubulin proteins. Alternative tubulin isotypes and a variety of post- translational modifications control the properties and functions of the microtubule cytoskeleton, a concept known as the ‘tubulin code’. Here we review the current understanding of the molecular components of the tubulin code and how they impact microtubule properties and functions. We discuss how tubulin isotypes and post-translational modifications control microtubule behaviour at the molecular level and how this translates into physiological functions at the cellular and organism levels. We then go on to show how fine-tuning of microtubule function by some tubulin modifications can affect homeostasis and how perturbation of this fine- tuning can lead to a range of dysfunctions, many of which are linked to human disease. 20 Axonemes Microtubules are cytoskeletal filaments with an outer cellular structures . Other MAPs bind to the micro- A tubular structure built from diameter of approximately 25 nm, and are composed of tubule lattice along its entire length and are thus con- microtubules and associated heterodimers of globular α- tubulin and β- tubulin mol- sidered to regulate microtubule dynamics and stability, proteins at the core of all ecules. As they are hollow cylinders, microtubules are but might also have additional roles that in many cases eukaryotic cilia and flagella. 1 21 In motile cilia and flagella, mechanically rigid , thus allowing their assembly into remain to be explored . In addition, active molecular the axoneme consists of nine large intracellular structures. These structures are essen- motors either carry cargos along microtubules or gener- microtubule doublets arranged tial for cell function and include mitotic and meiotic ate forces within microtubule assemblies. Specific com- around a central microtubule spindles, which ensure the correct division of cells2–4, binations of non- motile MAPs and molecular motors pair, accessory proteins and axonemes, which are the central molecular machines can therefore explain the mechanisms underlying axonemal dynein motors that 5–7 ensure the beating of cilia. of cilia and flagella , and the neuronal cytoskeleton, self- organizing assemblies such as mitotic and meiotic 22,23 Primary cilia lack the motor which controls the connectivity and function of neu- spindles , or the highly controlled wave- like beating protein and central- pair rons8–10. Microtubules are intrinsically dynamic as they of flagellar axonemes24,25. microtubules. can alternate between phases of polymerization and By contrast, how the incorporation of specific spontaneous depolymerization in a process known as α- tubulin or β- tubulin variants (known as tubulin iso- dynamic instability11. How the cell tames this fluctuating types) or the post- translational modification (PTM) system into highly ordered and controlled structures has of tubulins can functionally modulate microtubules been studied by a large scientific community for more remained mostly unexplained until the beginning of than half a century12. the twenty-first century. The concept that molecular pat- Since the early ultrastructural analyses of micro- terns generated by combinations of tubulin isotypes and 13,14 26 1Institut Curie, PSL Research tubules by electron microscopy , advances have been PTMs, termed the ‘tubulin code’ , could control micro- University, CNRS UMR3348, made towards understanding how nearly identical tubule functions was proposed as early as the 1970s27,28, Orsay, France. microtubules made of highly conserved α–β- tubulin but resisted a thorough functional characterization for 2Université Paris- Saclay, heterodimers can carry out such diverse cellular func- many years. Recent advances revealed that the tubulin CNRS UMR3348, Orsay, tions15–19. Microtubules do not function alone; they code acts in many instances as a fine regulator, and not France. interact with a diverse array of microtubule- associated as a binary switch, of microtubule functions. While this ✉e- mail: [email protected]; proteins (MAPs) that influence their assembly and might have only a minor impact at the level of single [email protected] dynamics. Some MAPs specifically bind to the plus or cells, dysfunction of these fine- tuning mechanisms can https://doi.org/10.1038/ the minus ends of microtubules to control microtubule lead to massive perturbations of homeostasis and even- s41580-020-0214-3 dynamics and the attachment of microtubules to other tually result in disease. In this Review we summarize the NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 21 | JUNE 2020 | 307 REVIEWS Marginal band current understanding of the tubulin code, its elements Tubulin isotypes A microtubule coil of precisely and their regulation and discuss the functional implica- Tubulin isotypes arise from the expression of alter- 12 turns at the outer rim of tions of the tubulin code for the cell and for the organism native tubulin genes, and their numbers differ largely blood platelets. as a whole. between species and phyla. In yeast, for example, two genes encode α-tubulin 31, and only one gene encodes Elements of the tubulin code β- tubulin32, whereas the human genome contains nine Microtubules exist in every eukaryotic cell. The striking genes for each33. There is no clear evolutionary trajectory sequence conservation of tubulins throughout evolution of these tubulin genes, which is why orthologues can be is reflected by their near identical structure across vir- identified only in evolutionarily close species. This fact tually every species in which tubulin structure has been is reflected in the confusing nomenclature of the tubulin investigated so far29,30. Tubulin across all eukaryotic genes34. ‘Generic’ α- tubulin and β- tubulin isotypes are organisms assembles into microtubules, hollow tubes that highly conserved between evolutionarily distant species, are most often built of 13 chains of stacked α–β- tubulin whereas less common isotypes appear to have evolved dimers known as protofilaments. Despite their high as novel microtubule functions arose. For example, degree of evolutionary conservation, micro tubules can β1- tubulin (encoded by TUBB1) has co- evolved35 with show different behaviours, properties or even struc- platelets, small cell fragments essential for blood coagu- tures between species and cell types or even within sin- lation that are unique to mammals. Platelets assemble a gle cells owing to the incorporation of different tubulin specialized microtubule array called the ‘marginal band’, isotypes and their PTM. which requires β1- tubulin36, a highly divergent isotype in the vertebrate phylum. Tubulin isotypes Tubulin post-translational modifications In Drosophila melanogaster, β3- tubulin (encoded by β β βTub60D) is expressed in subsets of cells during devel- β α β α Polyamination 37 α β opment . Gene knock- in experiments demonstrated α α Am that this isotype cannot replace the generic β2- tubulin Polyglutamylation Am Phosphorylation (encoded by βTub85D) in key microtubule functions in Am s P Side chain E the testes, such as axoneme assembly or spindle forma- Q15 E β S172 E tion38, suggesting that β3-tubulin had evolved to regulate E E specific microtubule functions in the fly. E G E E E E D Although these examples show that some isotypes are Ac K252 Q F G E ubulin dimer G E A T G essential to form functionally specialized microtubule E G E G arrays, it is unclear why so many tubulin isotypes are β almost identical across many species, including mammals. α Branching α points We consider this question in this Review. β Acetylation α ∆2-tubulin and otubule β K40 Ac E ∆3-tubulin Tubulin PTMs α E E Micr G E Tubulin is subjected to a large number of PTMs (FIg. 1; E Y Tyrosination β E E E α G E E E G TAble 1). Some of these modifications, such as phospho- Detyrosination 39–55 56 57 β Tubulin G rylation , acetylation , methylation , palmitoyl- G α body G 58 59,60 61 G ation , ubiquitylation and polyamination are found β Side chain Polyglycylation α on a broad range of proteins; others were initially discov- ered on tubulin. Examples of such PTMs are the enzy- C-terminal tails matic, ribosome-independent incorporation of tyrosine In microtubule (tyrosination)62,63, glutamate (glutamylation and polyglu- lumen tamylation)64–66 and glycine (glycylation and polyglycyl- ation)67. Moreover, enzymatic removal of single amino Fig. 1 | The elements of the tubulin code. Microtubules dynamically assemble from acids, such as tyrosine from the C terminus of α-tubulin dimers of α- tubulins and β- tubulins. Tubulins are highly structured proteins, forming 68,69 70,71 ‘tubulin bodies’, whereas their C- terminal amino acids form unstructured tails that (detyrosination) , or generation of ∆2-tubulin or 72 protrude from the microtubule surface. The tubulin code refers to the concept ∆3-tubulin through subsequent removal of glutamate that different tubulin gene products, together with a variety of post- translational residues from the detyrosinated α-tubulin C terminus modifications (PTMs), modulate the composition of individual microtubules. Tubulin (BOx

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