TTC5 mediates autoregulation of tubulin via mRNA degradation

Abstract

Tubulins play crucial roles in cell division, intracellular traffic, and cell shape. Tubulin concentration is autoregulated by feedback control of messenger RNA (mRNA) degradation via an unknown mechanism. We identified tetratricopeptide protein 5 (TTC5) as a tubulin-specific ribosome-associating factor that triggers cotranslational degradation of tubulin mRNAs in response to excess soluble tubulin. Structural analysis revealed that TTC5 binds near the ribosome exit tunnel and engages the amino terminus of nascent tubulins. TTC5 mutants incapable of ribosome or nascent tubulin interaction abolished tubulin autoregulation and showed chromosome segregation defects during mitosis. Our findings show how a subset of mRNAs can be targeted for coordinated degradation by a specificity factor that recognizes the nascent polypeptides they encode.

Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

“…Opposing changes in STK11 protein and mRNA levels could reflect homeostatic control of this powerful signaling pathway. Translation-dependent feedback of some other proteins is known to reduce mRNA levels through nonsense-mediated decay ( Giorgi et al, 2007 ; Paolantoni et al, 2018 ) or other forms of mRNA degradation ( Lin et al, 2020 ; Shoshani and Cleveland, 2020 ). Complex feedback control involving changes in RNA export and stability has also been described for MAP kinase signaling ( Sugiura et al, 2003 ; Prieto-Ruiz et al, 2020 ), but whether this type of regulation exists for Stk11 and the AMP-related kinase pathway remains unknown.…”

Tubulin mutations in neurodevelopmental disorders as a tool to decipher microtubule function

“…Secondly, the mutated tubulin produced could be unstable and/or unable to assemble into MTs, so that in effect, mutations therefore behave as typical 'loss‐of‐function' mutations. In this case, one could imagine that transcomplementation would occur with the intact allele, as well as with other isoforms, as suggested by the data showing that cells can detect and strikingly maintain soluble tubulin concentration [49–51]. Indeed, this is what is observed when both alleles of the neuronal gene TUBB3 are deleted in mice with no detectable variation in β‐tubulin level [167].…”

“…showed early on that a sudden increase in the free tubulin pool of cells treated with specific MT inhibitors leads to a rapid decrease in tubulin synthesis [49]. More recently, it was shown that quiescent cells are able to detect both subtle and strong perturbations in MT dynamics, and to maintain the concentration of soluble tubulin through cotranslational degradation of excess tubulin RNA by a ribosomal protein, TTC5 [50,51].…”

4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay

“…Tubulin mRNAs are co-translationally degraded in cells with excess soluble subunits (Cleveland et al, 1981;Lin et al, 2020). TUBA4A and TUBB4A are 4EHP and GIGYF1/2 target mRNAs (Tables S2, S3, and S4).…”