<scp><i>RBCK1</i></scp>‐related disease: A rare multisystem disorder with polyglucosan storage, auto‐inflammation, recurrent infections, skeletal, and cardiac myopathy—Four additional patients and a review of the current literature

Phadke, Rahul; Hedberg‐Oldfors, Carola; Scalco, R.; Lowe, David M.; Ashworth, Michael; Novelli, Marco; Vara, Roshni; Merwick, Áine; Amer, Halima; Sofat, Reecha; Sugarman, Max; Jovanović, Ana; Roberts, Mark; Nakou, Vasiliki; King, Andrew; Bódi, István; Jungbluth, Heinz; Oldfors, Anders; Murphy, Elaine

doi:10.1002/jimd.12234

Cited by 26 publications

(35 citation statements)

References 20 publications

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“…This plasticity in the composition of myddosomes adds to the difficulty in elucidating the molecular basis for the diverse effects on cytokine production caused by the loss of ester‐linked ubiquitylation in different immune cells. The present study has not only highlighted the potential importance of IRAK2 ubiquitylation but also begun to explain why loss of the E3 ligase activity of HOIL‐1 can cause immunodeficiency and auto‐inflammation [51,52].…”

Section: Discussionmentioning

confidence: 99%

HOIL‐1‐catalysed, ester‐linked ubiquitylation restricts IL‐18 signaling in cytotoxic T cells but promotes TLR signalling in macrophages

et al. 2021

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The atypical E3 ligase HOIL-1 forms ester bonds between ubiquitin and serine/threonine residues in proteins, but the physiological roles of this unusual modification are unknown. We now report that IL-18 signalling leading to the production of interferon c (IFNc) and granulocyte-macrophage colony-stimulating factor (GM-CSF) is enhanced in cytotoxic T cells from knock-in mice expressing the E3 ligase-inactive HOIL-1[C458S] mutant, demonstrating that the formation of HOIL-1-catalysed ester-linked ubiquitin bonds restricts the activation of this pathway. We show that the interaction of IRAK2 with TRAF6 is required for IL-18-stimulated IFN-c and GM-CSF production, and that the increased production of these cytokines in cytotoxic T cells from HOIL-1[C458S] mice correlates with an increase in both the number and size of the Lys63/Met1-linked hybrid ubiquitin chains attached to IRAK2 in these cells. In contrast, the secretion of IL-12 and IL-6 and the formation of il-12 and il-6 mRNA induced in bone marrow-derived macrophages (BMDMs) by prolonged stimulation with TLR-activating ligands that signal via myddosomes, which also requires the interaction of IRAK2 with TRAF6, were not increased but modestly reduced in HOIL-1[C458S] BMDM. The decreased production of these cytokines correlated with reduced ubiquitylation of IRAK2. Our results establish that changes in HOIL-1-catalysed ester-linked ubiquitylation can promote or reduce cytokine production depending on the ligand, receptor and immune cell and may be explained by differences in the ubiquitylation of IRAK2.

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Section: Discussionmentioning

confidence: 99%

HOIL‐1‐catalysed, ester‐linked ubiquitylation restricts IL‐18 signaling in cytotoxic T cells but promotes TLR signalling in macrophages

et al. 2021

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“…Compared with only two patients with HOIP, multiple patients have been reported with homozygous or compound heterozygous mutations in the HOIL-1L gene [ 21 ]. OMIM has registered HOIL-1L deficiency as PGBM1 WITH OR WITHOUT IMMUNODEFICIENCY (OMIM entry #615895).…”

Section: Lubac and Pb Diseasementioning

confidence: 99%

“…Using in vitro experiments, malin was shown to incorporate lysine 48 (K48) or K63-linked ubiquitin chains on substrates leading to their proteasomal or autophagosomal degradation [20]. (B) HOIL-1L deficiency results in a disease in which polyglucosans accumulate in skeletal and cardiac muscle, resulting in skeletal and cardiomyopathy and heart failure necessitating cardiac transplantation [21]. While all HOIL-1L deficient patients accumulate polyglucosans, some depending on the mutation, also Ubiquitin is transferred from E1 to E2 and finally to one of three types of E3 ubiquitin ligases.…”

Section: Introductionmentioning

confidence: 99%

LUBAC: a new player in polyglucosan body disease

Aboujaoude

Minassian

Mitra

2021

Biochemical Society Transactions

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Altered protein ubiquitination is associated with the pathobiology of numerous diseases; however, its involvement in glycogen metabolism and associated polyglucosan body (PB) disease has not been investigated in depth. In PB disease, excessively long and less branched glycogen chains (polyglucosan bodies, PBs) are formed, which precipitate in different tissues causing myopathy, cardiomyopathy and/or neurodegeneration. Linear ubiquitin chain assembly complex (LUBAC) is a multi-protein complex composed of two E3 ubiquitin ligases HOIL-1L and HOIP and an adaptor protein SHARPIN. Together they are responsible for M1-linked ubiquitination of substrates primarily related to immune signaling and cell death pathways. Consequently, severe immunodeficiency is a hallmark of many LUBAC deficient patients. Remarkably, all HOIL-1L deficient patients exhibit accumulation of PBs in different organs especially skeletal and cardiac muscle resulting in myopathy and cardiomyopathy with heart failure. This emphasizes LUBAC's important role in glycogen metabolism. To date, neither a glycogen metabolism-related LUBAC substrate nor the molecular mechanism are known. Hence, current reviews on LUBAC's involvement in glycogen metabolism are lacking. Here, we aim to fill this gap by describing LUBAC's involvement in PB disease. We present a comprehensive review of LUBAC structure, its role in M1-linked and other types of atypical ubiquitination, PB pathology in human patients and findings in new mouse models to study the disease. We conclude the review with recent drug developments and near-future gene-based therapeutic approaches to treat LUBAC related PB disease.

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“…Mutations that reduce the expression of HOIL-1 (haem-oxidised IRP2 ubiquitin ligase-1), also called RBCK1 (RING-B-Box-coiled-coil protein interacting with PKC 1 or RANBP2-Type and C3HC4-type zinc finger-containing protein 1) cause both auto-inflammation and immuno-insufficiency in humans (Boisson et al, 2012;Phadke et al, 2020) and immunoinsufficiency in mice (MacDuff et al, 2015;Tokunaga et al, 2009). However, HOIL-1 deficiency in humans also leads to cardiomyopathy and death from heart failure in early adulthood (Boisson et al, 2012;Fanin et al, 2015;Krenn et al, 2018;Nilsson et al, 2013;Phadke et al, 2020;Wang et al, 2013), which is unrelated to the immune defects, and arises from the progressive accumulation of toxic polyglucosan bodies in cardiac muscle and other tissues, such as the brain, with some patients also displaying cognitive impairment (Chen et al, 2021;Phadke et al, 2020). Mice expressing low levels of HOIL-1 (Fujita et al, 2018) also form toxic polyglucosan bodies in cardiac muscle (MacDuff et al, 2015), brain and spinal cord (Sullivan et al, 2018), but it is the brain that is affected predominantly in mice, the animals displaying defects in learning, memory and motor coordination (Sullivan et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

HOIL-1-catalysed ubiquitylation of unbranched glucosaccharides and its activation by ubiquitin oligomers

Kelsall

McCrory

et al. 2021

Preprint

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HOIL-1, a component of the Linear Ubiquitin Assembly Complex (LUBAC), ubiquitylates serine and threonine residues in proteins, forming ester bonds (Kelsall et al, 2019, PNAS 116, 13293-13298). Here we report that mice expressing the E3 ligase-inactive HOIL-1[C458S] mutant accumulate polyglucosan in brain, cardiac muscle and other organs, indicating that HOIL-1's E3 ligase activity is essential to prevent these toxic polysaccharide deposits from accumulating. We found that HOIL-1 monoubiquitylates glycogen and α1:4-linked maltoheptaose in vitro and identify the C6 hydroxyl moiety of glucose as the site of ester-linked ubiquitylation. The HOIL-1-catalysed monoubiquitylation of maltoheptaose was accelerated >100-fold by Met1-linked or Lys63-linked ubiquitin oligomers, which interact with the catalytic RBR domain of HOIL-1. HOIL-1 also transferred preformed ubiquitin oligomers to maltoheptaose en bloc, producing polyubiquitylated maltoheptaose in one catalytic step. The Sharpin and HOIP components of LUBAC, but not HOIL-1, bound to amylose resin in vitro, suggesting a potential function in targeting HOIL-1 to unbranched glucosaccharides in cells. We suggest that monoubiquitylation of unbranched glucosaccharides may initiate their removal by glycophagy to prevent precipitation as polyglucosan.

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RBCK1‐related disease: A rare multisystem disorder with polyglucosan storage, auto‐inflammation, recurrent infections, skeletal, and cardiac myopathy—Four additional patients and a review of the current literature

Cited by 26 publications

References 20 publications

HOIL‐1‐catalysed, ester‐linked ubiquitylation restricts IL‐18 signaling in cytotoxic T cells but promotes TLR signalling in macrophages

HOIL‐1‐catalysed, ester‐linked ubiquitylation restricts IL‐18 signaling in cytotoxic T cells but promotes TLR signalling in macrophages

LUBAC: a new player in polyglucosan body disease

HOIL-1-catalysed ubiquitylation of unbranched glucosaccharides and its activation by ubiquitin oligomers

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