Emerging roles for Lys11-linked polyubiquitin in cellular regulation

Bremm, Anja; Komander, David

doi:10.1016/j.tibs.2011.04.004

Cited by 64 publications

(74 citation statements)

References 71 publications

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“…UbcH10, a ubiquitination-initiating E2 enzyme, and Ube2S, a ubiquitin chain-elongating E2 enzyme, both work with the APC/ C E3 ubiquitin ligase to form Lys11-linked chains on APC/C substrates 23,32 . Reportedly, multiple monoubiquitination by UbcH10 is sufficient for APC/C-dependent degradation of cyclin B1, which carries numerous ubiquitinatable Lys residues in the N terminus 30 .…”

Section: Resultsmentioning

confidence: 99%

“…In higher eukaryotes including vertebrates, the APC/C assembles Lys11-linked ubiquitin chains on APC/C substrates by utilizing two different E2 ubiquitin-conjugating enzymes, UbcH10 and Ube2S [22][23][24] . UbcH10 is responsible primarily for monoubiquitination (or initiation of polyubiquitination) of APC/C substrates 24,25 , whereas Ube2S catalyses ubiquitin chain elongation (or polyubiquitination) of the monoubiquitinated APC/C substrates [26][27][28] .…”

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confidence: 99%

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Emi2 mediates meiotic MII arrest by competitively inhibiting the binding of Ube2S to the APC/C

et al. 2014

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Emi2 mediates meiotic MII arrest by competitively inhibiting the binding of Ube2S to the APC/C

et al. 2014

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“…While the role of K48 ubiquitin in targeting cytosolic and ER proteins for degradation has been known for some time, the importance of K11 ubiquitination has only recently been appreciated [21]. A hint that K11 ubiquitin might be involved with p97 came from a proteomic analysis of the UBA-UBX protein interaction network, which were enriched for K11 linked ubiquitin [26].…”

Section: Discussionmentioning

confidence: 99%

“…K11 ubiquitin linkages have recently been implicated in diverse cellular pathways (reviewed in [21]). A proteomic study found that K11 chains accumulate with ER stress in budding yeast, indicating a role in maintaining ER homeostasis [22].…”

Section: Introductionmentioning

confidence: 99%

Lys11- and Lys48-linked ubiquitin chains interact with p97 during endoplasmic-reticulum-associated degradation

Locke

Toth

Petroski

2014

Biochemical Journal

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The AAA+ ATPase p97 has a critical function in the cytoplasmic degradation of proteins misfolded in the endoplasmic reticulum through a mechanism known as ER-associated degradation (ERAD). During this process, p97 binds polyubiquitinated ERAD substrates and couples ATP hydrolysis to their dislocation from the ER as a prerequisite to destruction by the proteasome. The ubiquitin signals important for this process are not fully understood. Here we report that p97 interacts with lysine 11 (K11) and K48-linked ubiquitin polymers, but not those containing K63 linkages. Disruption of p97 through siRNA-mediated depletion, dominant negative over-expression, or chemical inhibition results in the accumulation of K11 and K48 ubiquitin chains predominantly at the ER membrane, and is associated with ER stress induction. We show that a catalytically inactive deubiquitinating enzyme and p97 cofactor YOD1 enhances the accumulation of K11- and K48-linked polyubiquitin in the cytoplasm, at the ER membrane, and bound to p97. In addition to general effects on p97-associated ubiquitin polymers, the ERAD substrate CD3δ is modified with both K11- and K48-ubiquitin chains prior to p97-dependent dislocation. Collectively, our data are consistent with a major role for p97 in the recognition of K11 and K48 polyubiquitinated proteins prior to their degradation by the proteasome.

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“…K6-polyubiquitination is linked to DNA repair processes, 11 while K11 is linked to development and other roles associated with cell division and ERAD. 12,13 Very recent findings revealed mostly non-proteolytic roles for K27-, K29-, and K33-polyUbs, including innate immune system regulation for K27- and K33-polyUbs 14–16 , and regulation of mRNA stability for K29-polyUb, among others. 17–19 …”

Section: Introductionmentioning

confidence: 99%

Linkage-specific conformational ensembles of non-canonical polyubiquitin chains

Castañeda

Chaturvedi

Camara

et al. 2016

Phys. Chem. Chem. Phys.

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Polyubiquitination is a critical protein post-translational modification involved in a variety of processes in eukaryotic cells. The molecular basis for selective recognition of the polyubiquitin signals by cellular receptors is determined by the conformations polyubiquitin chains adopt; this has been demonstrated for K48- and K63-linked chains. Recent studies of the so-called non-canonical chains (linked via K6, K11, K27, K29, or K33) suggest they play important regulatory roles in growth, development, and immune system pathways, but biophysical studies are needed to elucidate the physical/structural basis of their interactions with receptors. A first step towards this goal is characterization of the conformations these chains adopt in solution. We assembled diubiquitins (Ub2) comprised of every lysine linkage. Using solution NMR measurements, small-angle neutron scattering (SANS), and in silico ensemble generation, we determined population-weighted conformational ensembles that shed light on the structure and dynamics of the non-canonical polyubiquitin chains. We found that polyubiquitin is conformationally heterogeneous, and each chain type exhibits unique conformational ensembles. For example, K6-Ub2 and K11-Ub2 (at physiological salt concentration) are in dynamic equilibrium between at least two conformers, where one exhibits a unique Ub/Ub interface, distinct from that observed in K48-Ub2 but similar to crystal structures of these chains. Conformers for K29-Ub2 and K33-Ub2 resemble recent crystal structures in the ligand-bound state. Remarkably, a number of diubiquitins adopt conformers similar to K48-Ub2 or K63-Ub2, suggesting potential overlap of biological function among different lysine linkages. These studies highlight the potential power of determining function from elucidation of conformational states.

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Emerging roles for Lys11-linked polyubiquitin in cellular regulation

Cited by 64 publications

References 71 publications

Emi2 mediates meiotic MII arrest by competitively inhibiting the binding of Ube2S to the APC/C

Emi2 mediates meiotic MII arrest by competitively inhibiting the binding of Ube2S to the APC/C

Lys11- and Lys48-linked ubiquitin chains interact with p97 during endoplasmic-reticulum-associated degradation

Linkage-specific conformational ensembles of non-canonical polyubiquitin chains

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