Dataset Information

Sugar-Recognizing Ubiquitin Ligases: Action Mechanisms and Physiology.

ABSTRACT: F-box proteins, the substrate recognition subunits of SKP1-CUL1-F-box protein (SCF) E3 ubiquitin ligase complexes, play crucial roles in various cellular events mediated by ubiquitination. Several sugar-recognizing F-box proteins exist in both mammalian and plant cells. Although glycoproteins generally reside outside of cells, or in organelles of the secretory pathway, these lectin-type F-box proteins reside in the nucleocytoplasmic compartment. Mammalian sugar-recognizing F-box proteins commonly bind to the innermost position of N-glycans through a unique small hydrophobic pocket in their loops. Two cytosolic F-box proteins, Fbs1 and Fbs2, recognize high-mannose glycans synthesized in the ER, and SCFFbs1 and SCFFbs2 ubiquitinate excess unassembled or misfolded glycoproteins in the ERAD pathway by recognizing the innermost glycans, which serve as signals for aberrant proteins. On the other hand, endomembrane-bound Fbs3 recognizes complex glycans as well as high-mannose glycans, and SCFFbs3 ubiquitinates exposed glycoproteins in damaged lysosomes fated for elimination by selective autophagy. Plants express stress-inducible lectin-type F-box proteins recognizing a wider range of N- and O-glycans, suggesting that the roles of mammalian and plant lectin-type F-box proteins have diverged over the course of evolution to recognize species-specific targets with distinct functions. These sugar-recognizing F-box proteins interpret glycans in the cytosol as markers of unwanted proteins and organelles, and degrade them via the proteasome or autophagy.

SUBMITTER: Yoshida Y

PROVIDER: S-EPMC6389600 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Sugar-Recognizing Ubiquitin Ligases: Action Mechanisms and Physiology.

Yoshida Yukiko Y Mizushima Tsunehiro T Tanaka Keiji K

Frontiers in physiology 20190219

F-box proteins, the substrate recognition subunits of SKP1-CUL1-F-box protein (SCF) E3 ubiquitin ligase complexes, play crucial roles in various cellular events mediated by ubiquitination. Several sugar-recognizing F-box proteins exist in both mammalian and plant cells. Although glycoproteins generally reside outside of cells, or in organelles of the secretory pathway, these lectin-type F-box proteins reside in the nucleocytoplasmic compartment. Mammalian sugar-recognizing F-box proteins commonl ...[more]

PMID: 30837888

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Project description:In eukaryotes many players in the DNA-damage response (DDR) catalyze protein sumoylation or ubiquitylation. Emphasis has been placed on how these modifications orchestrate the sequential recruitment of repair factors to sites of DNA damage or stalled replication forks. Here, we shed light on a pathway in which sumoylated factors are eliminated through the coupled action of Sumo-targeted ubiquitin ligases (STUbLs) and the ubiquitin-fusion degradation protein 1 (Ufd1). Ufd1 is a subunit of the Cdc48-Ufd1-Npl4 complex implicated in the sorting of ubiquitylated substrates for degradation by the proteasome. We find that in fission yeast, Ufd1 interacts physically and functionally with the Sumo-targeted ubiquitin ligase (STUbL) Rfp1, homologous to human RNF4, and with the Sumo E3 ligase Pli1, homologous to human PIAS1. Deleting a C-terminal domain of Ufd1 that mediates the interaction of Ufd1 with Rfp1, Pli1, and Sumo (ufd1?Ct(213-342) ) lead to an accumulation of high-molecular-weight Sumo conjugates and caused severe genomic instabilities. The spectrum of sensitivity of ufd1?Ct(213-342) cells to genotoxins, the epistatic relationships of ufd1?Ct(213-342) with mutations in DNA repair factors, and the localization of the repair factor Rad22 in ufd1?Ct(213-342) cells point to ufd1?Ct(213-342) cells accumulating aberrant structures during replication that require homologous recombination (HR) for their repair. We present evidence that HR is however often not successful in ufd1?Ct(213-342) cells and we identify Rad22 as one of the high-molecular-weight conjugates accumulating in the ufd1?Ct(213-342) mutant consistent with Rad22 being a STUbL/Ufd1 substrate. Suggesting a direct role of Ufd1 in the processing of Sumo-conjugates, Ufd1 formed nuclear foci colocalizing with Sumo during the DDR, and Sumo-conjugates accumulated in foci in the ufd1?Ct(213-342) mutant. Broader functional relationships between Ufd1 and STUbLs conceivably affect numerous cellular processes beyond the DDR.

Dataset Information

Sugar-Recognizing Ubiquitin Ligases: Action Mechanisms and Physiology.

Publications

Sugar-Recognizing Ubiquitin Ligases: Action Mechanisms and Physiology.

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