T cell proliferation requires ribosomal maturation in nucleolar condensates dependent on DCAF13

Abstract

T cells require rapid proliferation to initiate adaptive immunity to prevent pathogen attacks. The nucleolus, a distinct subnuclear membrane-less compartment for ribosomal biogenesis, is indispensable for cell proliferation. However, specific nucleolar proteins involved in rapid T cell proliferation and their underlying molecular regulatory mechanism remain elusive. Here, we identified an essential nucleolar protein, DCAF13, in T cells and revealed its significant regulation of rapid T cell proliferation. Its depletion drastically impairs T cell proliferation due to severe 18S rRNA maturation failure, consequent abnormal ribosome assembly in nucleoli, and insufficient production of nascent proteins. Mechanistically, we propose that DCAF13 promotes NPM1 phase separation to accelerate pre-RNA enrichment and its endonuclease UTP23 for 18S rRNA maturation during T cell proliferation. Our findings reveal the modulatory effect of nucleolar NPM1/DCAF13 phase separation on ribosomal maturation to ensure rapid T cell proliferation and further pathogen clearance for the first time.

Nucleolar condensates: A cellular machinery necessary for T cell activation

“…During activation, T cells prepare for significant protein needs in part by synthesizing new ribosomes. In this issue of JCB , Zhou et al ( 1 ) characterize the role of the nucleolar protein DCAF13 (DDB1 and CUL4 Associated Factor 13) during T cell activation and define its role in accelerating ribosomal maturation via its ability to phase separate with nucleophosmin 1 (NPM1; Fig. 1 ).…”

“…Zhou et al used the activation of naive T cells as a model to study the dynamic changes that occur in the nucleolus during cell growth ( 1 ). They began by showing that during the activation of naive T cells, nucleoli increase in number and size, as well as changing shape.…”

“…To study its role in T cells, Zhou et al ( 1 ) generated a T cell specific DCAF13 KO mouse ( 9 ). While TCR development in the thymus appeared grossly normal, T cell numbers in the periphery decreased.…”

“…Zhou et al ( 1 ) mapped the interaction between DCAF13 and NPM1 and showed that DCAF13 interacted with NPM1 via its 30 residues at the C-terminal. They then tested its role in regulating NPM1 in the nucleolus.…”

“…NPM1 is concentrated in the outside layer of the nucleolus where final processing of rRNA and ribosomal assembly occurs ( 2 ). Since the final processing step of rRNA is mediated by the endonuclease, UTP23 ( 13 ), and because DCAF13 T cells lack the 18S rRNA generated by UTP23, Zhou et al ( 1 ) found that DCAF13/NPM1 condensates recruit UTP23.…”