Crucial Proteins for Maintaining Centriole Architecture: A Delta-Tubulin/Epsilon-Tubulin/TEDC1/TEDC2 Complex

Core Concepts

A tetrameric protein complex consisting of delta-tubulin, epsilon-tubulin, TEDC1, and TEDC2 is essential for the proper assembly and maintenance of centriole architecture, particularly the formation of triplet microtubules.

Abstract

The article investigates the mechanisms underlying the unique, conserved architecture of centrioles, which are composed of three linked "triplet" microtubules arranged in a nine-fold symmetry. The authors previously found that human cells deficient in delta-tubulin or epsilon-tubulin form abnormal centrioles, characterized by an absence of triplet microtubules, lack of central core protein POC5, and a futile cycle of centriole formation and disintegration.
In this study, the authors show that human cells lacking either of the associated proteins TEDC1 and TEDC2 exhibit the same phenotypes as those lacking delta-tubulin or epsilon-tubulin. Using ultrastructure expansion microscopy, the authors mapped the locations of centriolar proteins throughout the cell cycle and found that mutant centrioles have normal architecture during S-phase, but by G2-phase, they fail to recruit inner scaffold proteins of the central core. Instead, the inner lumen of the centrioles is filled with an expanded proximal region, indicating that these proteins or the triplet microtubules themselves may be required for recruiting central core proteins and restricting the length of the proximal end. During mitosis, the mutant centrioles elongate further before fragmenting and disintegrating.
The authors demonstrate that the four proteins (delta-tubulin, epsilon-tubulin, TEDC1, and TEDC2) physically interact, and TEDC1 and TEDC2 are capable of interacting in the absence of the tubulins. These results support an AlphaFold Multimer structural prediction model for the tetrameric complex, in which delta-tubulin and epsilon-tubulin are predicted to form a heterodimer. The authors also show that TEDC1 and TEDC2 localize to centrosomes and are mutually dependent on each other and on delta-tubulin and epsilon-tubulin for localization.
Overall, this work indicates that the delta-tubulin/epsilon-tubulin/TEDC1/TEDC2 complex is essential for promoting robust centriole architecture, particularly the formation and maintenance of triplet microtubules. The findings lay the groundwork for future dissection of this complex, which will provide insights into the mechanisms underlying the assembly and interplay between compound microtubules and inner centriole structure.

Stats

Human cells deficient in delta-tubulin or epsilon-tubulin form abnormal centrioles, characterized by an absence of triplet microtubules, lack of central core protein POC5, and a futile cycle of centriole formation and disintegration.
Human cells lacking either TEDC1 or TEDC2 exhibit the same phenotypes as those lacking delta-tubulin or epsilon-tubulin.
The four proteins (delta-tubulin, epsilon-tubulin, TEDC1, and TEDC2) physically interact, and TEDC1 and TEDC2 are capable of interacting in the absence of the tubulins.

Quotes

"Previously, we found that human cells deficient in delta-tubulin or epsilon-tubulin form abnormal centrioles, characterized by an absence of triplet microtubules, lack of central core protein POC5, and a futile cycle of centriole formation and disintegration."
"We find that mutant centrioles have normal architecture during S-phase. By G2-phase, mutant centrioles grow to the same length as control centrioles, but fail to recruit inner scaffold proteins of the central core. Instead, the inner lumen of centrioles is filled with an expanded proximal region, indicating that these proteins, or the triplet microtubules themselves, may be required for recruiting central core proteins and restricting the length of the proximal end."

Key Insights Distilled From

A delta-tubulin/epsilon-tubulin/Ted protein complex is required for centriole architecture

by Pudlowski,R.... at www.biorxiv.org 04-20-2024

https://www.biorxiv.org/content/10.1101/2024.04.19.590208v1

Deeper Inquiries

What are the specific roles of delta-tubulin and epsilon-tubulin in the formation and maintenance of triplet microtubules within centrioles?

Delta-tubulin and epsilon-tubulin play crucial roles in the formation and maintenance of triplet microtubules within centrioles. These noncanonical tubulins are essential for the proper assembly of the triplet microtubules, which are arranged in nine-fold symmetry to form the unique architecture of centrioles. Delta-tubulin and epsilon-tubulin are involved in providing structural support and stability to the triplet microtubules, ensuring the integrity of the centriolar structure. Their absence leads to the formation of abnormal centrioles lacking triplet microtubules, central core protein POC5, and results in a defective cycle of centriole formation and disintegration.

How do the interactions between TEDC1, TEDC2, delta-tubulin, and epsilon-tubulin regulate the recruitment of central core proteins and the length of the centriole's proximal end?

The interactions between TEDC1, TEDC2, delta-tubulin, and epsilon-tubulin play a critical role in regulating the recruitment of central core proteins and controlling the length of the centriole's proximal end. These proteins form a tetrameric complex that is essential for maintaining the structural integrity of centrioles. During the cell cycle, mutant centrioles lacking TEDC1, TEDC2, delta-tubulin, or epsilon-tubulin exhibit abnormal architecture. In G2-phase, mutant centrioles grow to the same length as control centrioles but fail to recruit inner scaffold proteins of the central core. Instead, the proximal end of the centrioles becomes expanded, indicating a disruption in the recruitment of central core proteins. These interactions are crucial for ensuring the proper assembly and organization of centriolar components.

What are the potential implications of the disruption of this tetrameric complex for cellular processes and human health, particularly in the context of centriole-related disorders or diseases?

The disruption of the tetrameric complex composed of TEDC1, TEDC2, delta-tubulin, and epsilon-tubulin can have significant implications for cellular processes and human health, especially in the context of centriole-related disorders or diseases. Mutations or deficiencies in any of these proteins can lead to the formation of abnormal centrioles with structural defects, impacting essential cellular functions such as cell division, ciliary assembly, and intracellular organization. Dysregulation of centriole architecture has been linked to various human diseases, including ciliopathies, microcephaly, and cancer. Understanding the mechanisms underlying the assembly and function of this tetrameric complex is crucial for developing targeted therapies for centriole-related disorders and advancing our knowledge of centriole biology in health and disease.