Identifying the ERAD ubiquitin E3 ligases for viral and cellular targeting of MHC class I

Boomen, Dick J. H. van den; Lehner, Paul J.

doi:10.1016/j.molimm.2015.07.005

Cited by 41 publications

(41 citation statements)

References 35 publications

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“…For select quantity control substrates, bona fide substrate-specific adaptors have been identified that bridge the substrate and ERAD machinery, functioning as substrate identification and recruitment factors. For example, the viral US2 and US11 proteins deliver major histocompatibility complex class I proteins to, respectively, the E3 ligase Trc8 (translocation in renal carcinoma on chromosome 8 protein) (167, 186) and TMEM129 (184, 186, 187). Other examples include the sterol-regulated recruitment of HMGCRtotheE3 ligase gp78 by Insig (insulin-induced gene protein) 1 and 2 (24, 155, 166) and the activation-dependent recruitment of inositol triphosphate receptors to the E3 ligase RNF170 by Erlin (endoplasmic reticulum lipid raft–associated protein) 1 and 2 (101, 135, 195).…”

Section: Erad Mechanismmentioning

confidence: 99%

Endoplasmic Reticulum–Associated Degradation and Lipid Homeostasis

2016

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The endoplasmic reticulum is the port of entry for proteins into the secretory pathway and the site of synthesis for several important lipids, including cholesterol, triacylglycerol, and phospholipids. Protein production within the endoplasmic reticulum is tightly regulated by a cohort of resident machinery that coordinates the folding, modification, and deployment of secreted and integral membrane proteins. Proteins failing to attain their native conformation are degraded through the endoplasmic reticulum–associated degradation (ERAD) pathway via a series of tightly coupled steps: substrate recognition, dislocation, and ubiquitin-dependent proteasomal destruction. The same ERAD machinery also controls the flux through various metabolic pathways by coupling the turnover of metabolic enzymes to the levels of key metabolites. We review the current understanding and biological significance of ERAD-mediated regulation of lipid metabolism in mammalian cells.

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Section: Erad Mechanismmentioning

confidence: 99%

Endoplasmic Reticulum–Associated Degradation and Lipid Homeostasis

2016

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“…Furthermore, SEL1L variants have been identified in human patients with autoimmune thyroid diseases (Ban et al, ), Alzheimer's (Saltini et al, ), Sjögren's syndrome (Barrera et al, ) and in cardiovascular pathogenesis (Kraus et al, ). Viral degradation of MHC‐I chain also relies on the HRD1/SEL1L complex (van den Boomen & Lehner, ). In Finnish Hound dogs, mSEL‐1L was proposed to be a candidate gene responsible for early‐onset progressive cerebellar ataxia (Kyostila et al, ).…”

Section: Introductionmentioning

confidence: 99%

mSEL‐1L deficiency affects vasculogenesis and neural stem cell lineage commitment

Cardano¹,

Diaferia²,

Conti

et al. 2017

Journal Cellular Physiology

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mSEL-1L is a highly conserved ER-resident type I protein, involved in the degradation of misfolded peptides through the ubiquitin-proteasome system (UPS), a pathway known to control the plasticity of the vascular smooth muscle cells (VSMC) phenotype and survival. In this article, we demonstrate that mSEL-1L deficiency interferes with the murine embryonic vascular network, showing particular irregularities in the intracranic and intersomitic neurovascular units and in the cerebral capillary microcirculation. During murine embryogenesis, mSEL-1L is expressed in cerebral areas known to harbor progenitor neural cells, while in the adult brain the protein is specifically restricted to the stem cell niches, co-localizing with Sox2 and Nestin. Null mice are characterized by important defects in the development of telenchephalic regions, revealing conspicuous aberration in neural stem cell lineage commitment. Moreover, mSEL-1L depletion in vitro and in vivo appears to affect the harmonic differentiation of the NSCs, by negatively influencing the corticogenesis processes. Overall, the data presented suggests that the drastic phenotypic characteristics exhibited in mSEL-1L null mice can, in part, be explained by the negative influence it plays on Notch1 signaling pathway.

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“…US11 requires the ERAD machinery defined by the E2-recruitment protein AUP1, UBXD8 (ubiquitin regulatory X domain 8) [ 18 ], the E3 ligase TMEM129 [ 19 , 20 ], the E2 ubiquitin-conjugating enzyme Ube2J2 [ 19 , 20 ], and the polytopic membrane protein Derlin1 [ 21 , 22 ]. Although the ERAD adapter SEL1L [ 23 ] had previously been linked to US11 function, later work suggested that SEL1L may instead be involved in the degradation of US11 itself [ 24 ], US2 operates with a different set of cellular factors. The E3 ligase RNF139 (TRC8) [ 25 ] is required for US2 function and the thiol oxidoreductase PDI is thought to aid in the release of MHC I heavy chains from US2 prior to their degradation [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Cyclophilin C Participates in the US2-Mediated Degradation of Major Histocompatibility Complex Class I Molecules

2015

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Human cytomegalovirus uses a variety of mechanisms to evade immune recognition through major histocompatibility complex class I molecules. One mechanism mediated by the immunoevasin protein US2 causes rapid disposal of newly synthesized class I molecules by the endoplasmic reticulum-associated degradation pathway. Although several components of this degradation pathway have been identified, there are still questions concerning how US2 targets class I molecules for degradation. In this study we identify cyclophilin C, a peptidyl prolyl isomerase of the endoplasmic reticulum, as a component of US2-mediated immune evasion. Cyclophilin C could be co-isolated with US2 and with the class I molecule HLA-A2. Furthermore, it was required at a particular expression level since depletion or overexpression of cyclophilin C impaired the degradation of class I molecules. To better characterize the involvement of cyclophilin C in class I degradation, we used LC-MS/MS to detect US2-interacting proteins that were influenced by cyclophilin C expression levels. We identified malectin, PDIA6, and TMEM33 as proteins that increased in association with US2 upon cyclophilin C knockdown. In subsequent validation all were shown to play a functional role in US2 degradation of class I molecules. This was specific to US2 rather than general ER-associated degradation since depletion of these proteins did not impede the degradation of a misfolded substrate, the null Hong Kong variant of α1-antitrypsin.

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Identifying the ERAD ubiquitin E3 ligases for viral and cellular targeting of MHC class I

Cited by 41 publications

References 35 publications

Endoplasmic Reticulum–Associated Degradation and Lipid Homeostasis

Endoplasmic Reticulum–Associated Degradation and Lipid Homeostasis

mSEL‐1L deficiency affects vasculogenesis and neural stem cell lineage commitment

Cyclophilin C Participates in the US2-Mediated Degradation of Major Histocompatibility Complex Class I Molecules

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