Elucidation of short linear motif-based interactions of the MIT and rhodanese domains of the ubiquitin-specific protease 8 DOI Creative Commons

Aimiliani Konstantinou,

Julia K. Varga,

Alicia Córdova-Pérez

et al.

Biology Direct, Journal Year: 2025, Volume and Issue: 20(1)

Published: May 6, 2025

Abstract Ubiquitin-specific protease 8 (USP8) is a deubiquitinating enzyme with essential functions in protein trafficking and stability. It multidomain protein, an N-terminal MIT (microtubule interacting trafficking) domain, followed by non-catalytic rhodanese (Rhod) long intrinsically disordered region, C-terminal catalytic domain. The domain of USP8 known to mediate protein-protein interactions through binding short linear motifs. Rhod also involved interactions, however detailed insights into these remain limited. In this study we explore the motif-based domains using combination proteomic peptide-phage display, peptide arrays deep mutational scanning. We show that can bind ligands general [DE][LIF]x{2,3}R[FYIL]xxL[LV] consensus motif. uncover peptide-binding define two distinct motifs (Rx[LI]xGxxxPxxL G[LV][DE][IM]WExKxxxLxE) for scanning different ligands. Using motif information, predict sites within interactors substrates validate array analysis. Our findings demonstrate both are be bound degenerate information on preference provide novel molecular recognition events underlie function enzyme.

Language: Английский

ZFP36-family RNA-binding proteins in regulatory T cells reinforce immune homeostasis DOI Creative Commons
Beatriz Sáenz‐Narciso, Sarah E. Bell, Louise S. Matheson

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 6, 2025

Abstract RNA binding proteins (RBP) of the ZFP36 family limit differentiation and effector functions CD4 CD8 T cells, but little is known their expression or function in regulatory (Treg) cells. By using Treg cell-restricted deletion Zfp36 members we identify role Zfp36l1 Zfp36l2 cells to maintain immune homeostasis. Mice with deficient these RBP display an inflammatory phenotype expansion numbers type-2 conventional dendritic follicular helper germinal center B elevated serum cytokines immunoglobulins. In absence , pool cycling CTLA-4 naïve reduced, are less sensitive IL-2 IL-7 more IFNγ. mice lacking both a single allele Ifng sufficient ameliorate pathology. Our results indicate that ZFP36L1 ZFP36L2 regulate availability IFNγ required for maintenance cell stability. Thus, multiple pathways enable enforce

Language: Английский

Citations

0
Elucidation of short linear motif-based interactions of the MIT and rhodanese domains of the ubiquitin-specific protease 8 DOI Creative Commons

Aimiliani Konstantinou,

Julia K. Varga,

Alicia Córdova-Pérez

et al.

Biology Direct, Journal Year: 2025, Volume and Issue: 20(1)

Published: May 6, 2025

Abstract Ubiquitin-specific protease 8 (USP8) is a deubiquitinating enzyme with essential functions in protein trafficking and stability. It multidomain protein, an N-terminal MIT (microtubule interacting trafficking) domain, followed by non-catalytic rhodanese (Rhod) long intrinsically disordered region, C-terminal catalytic domain. The domain of USP8 known to mediate protein-protein interactions through binding short linear motifs. Rhod also involved interactions, however detailed insights into these remain limited. In this study we explore the motif-based domains using combination proteomic peptide-phage display, peptide arrays deep mutational scanning. We show that can bind ligands general [DE][LIF]x{2,3}R[FYIL]xxL[LV] consensus motif. uncover peptide-binding define two distinct motifs (Rx[LI]xGxxxPxxL G[LV][DE][IM]WExKxxxLxE) for scanning different ligands. Using motif information, predict sites within interactors substrates validate array analysis. Our findings demonstrate both are be bound degenerate information on preference provide novel molecular recognition events underlie function enzyme.

Language: Английский

Citations

0