The Membrane-Associated MARCH E3 Ligase Family: Emerging Roles in Immune Regulation

Lin, Heng; Li, Shu; Shu, Hong‐Bing

doi:10.3389/fimmu.2019.01751

Cited by 88 publications

(70 citation statements)

References 129 publications

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“…Despite this, our bioinformatic analysis of the L. mexicana genome revealed numerous ubiquitin conjugation system components: 2 ubiquitin E1, 13 ubiquitin E2 and 79 E3 ligase genes, including 12 HECT E3s, 1 RBR E3, 5 U-box RING E3s, 57 RING and 4 RING-CH-type E3s. These numbers are similar to those of another single-celled eukaryote, S. cerevisiae, which has 1 E1, 11 E2s and 60-100 E3s, of which 5 are HECT E3s, 2 are RBR E3s, 2 are U-box E3s, one is a RING CH-type E3 and the rest are RING E3s [67,68]…”

Section: Discussionsupporting

confidence: 62%

“…These numbers are similar to those of another single-celled eukaryote, S . cerevisiae , which has 1 E1, 11 E2s and 60–100 E3s, of which 5 are HECT E3s, 2 are RBR E3s, 2 are U-box E3s, one is a RING CH-type E3 and the rest are RING E3s [ 67 , 68 ]. In contrast, humans have 2 E1s, 40 E2s and over 600 E3s, of which 28 are HECT E3s, around 15 are RBR E3s, 9 are U-box E3s, 11 are RING CH-type E3s and the rest are RING E3s [ 68 – 72 ].…”

Section: Discussionmentioning

confidence: 99%

“…cerevisiae , which has 1 E1, 11 E2s and 60–100 E3s, of which 5 are HECT E3s, 2 are RBR E3s, 2 are U-box E3s, one is a RING CH-type E3 and the rest are RING E3s [ 67 , 68 ]. In contrast, humans have 2 E1s, 40 E2s and over 600 E3s, of which 28 are HECT E3s, around 15 are RBR E3s, 9 are U-box E3s, 11 are RING CH-type E3s and the rest are RING E3s [ 68 – 72 ]. We also identified a putative SUMO E1 catalytic subunit (UBA2), a Nedd8 E1 catalytic subunit (UBA3), a SUMO E2 (UBC9) and a Nedd8 E2 (UBC12), although E1, E2 and E3 genes for Ubls were not extensively searched for.…”

Section: Discussionmentioning

confidence: 99%

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Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex

et al. 2020

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Post-translational modifications such as ubiquitination are important for orchestrating the cellular transformations that occur as the Leishmania parasite differentiates between its main morphological forms, the promastigote and amastigote. 2 E1 ubiquitin-activating (E1), 13 E2 ubiquitin-conjugating (E2), 79 E3 ubiquitin ligase (E3) and 20 deubiquitinating cysteine peptidase (DUB) genes can be identified in the Leishmania mexicana genome but, currently, little is known about the role of E1, E2 and E3 enzymes in this parasite. Bar-seq analysis of 23 E1, E2 and HECT/RBR E3 null mutants generated in promastigotes using CRISPR-Cas9 revealed numerous loss-of-fitness phenotypes in promastigote to amastigote differentiation and mammalian infection. The E2s UBC1/CDC34, UBC2 and UEV1 and the HECT E3 ligase HECT2 are required for the successful transformation from promastigote to amastigote and UBA1b, UBC9, UBC14, HECT7 and HECT11 are required for normal proliferation during mouse infection. Of all ubiquitination enzyme null mutants examined in the screen, Δubc2 and Δuev1 exhibited the most extreme loss-of-fitness during differentiation. Null mutants could not be generated for the E1 UBA1a or the E2s UBC3, UBC7, UBC12 and UBC13, suggesting these genes are essential in promastigotes. X-ray crystal structure analysis of UBC2 and UEV1, orthologues of human UBE2N and UBE2V1/UBE2V2 respectively, reveal a heterodimer with a highly conserved structure and interface. Furthermore, recombinant L. mexicana UBA1a can load ubiquitin onto UBC2, allowing UBC2-UEV1 to form K63-linked di-ubiquitin chains in vitro. Notably, UBC2 can cooperate in vitro with human E3s RNF8 and BIRC2 to form non-K63-linked polyubiquitin chains, showing that UBC2 can facilitate ubiquitination independent of UEV1, but association of UBC2 with UEV1 inhibits this ability. Our study demonstrates the dual essentiality of UBC2 and UEV1 in the differentiation and intracellular survival of L. mexicana and shows that the interaction between these two proteins is crucial for regulation of their ubiquitination activity and function.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex

et al. 2020

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“…The membrane‐associated RING‐CH (MARCH) family comprises E3 ubiquitin ligases located on the plasma and organelle membranes, consisting of an N‐terminal ring finger and zero, two, or more C‐terminal transmembrane domains (Bauer et al, 2017). Of the 11 members of the MARCH family, some play important roles in immune regulation, such as endoplasmic reticulum degradation, protein‐energy control, and membrane transport (Lin et al, 2019; Nakamura, 2011). MARCH1, expressed by antigen‐presenting cells (APCs), dendritic cells (DCs), and B cells in lymphoid tissues (e.g., the spleen), participates in the regulation of antigen presentation via the ubiquitination of major histocompatibility complex (MHC)‐II and CD86 (Corcoran et al, 2011; Wilson et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

5‐FU inhibits migration and invasion of CRC cells through PI3K/AKT pathway regulated by MARCH1

Wang

Yang

Dai

et al. 2020

Cell Biology International

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Colorectal cancer is a major health problem with a significant impact on the patients' quality of life. 5‐Fluorouracil is the most common chemotherapy drug used for this type of cancer. While its molecular mechanism is the inhibition of DNA synthesis via the inhibition of thymine nucleotide synthetase, its complete anticancer mechanism is not clear. Membrane‐associated RING‐CH‐1 (MARCH1) is an E3 ubiquitin ligase that plays an important role in antigen presentation. However, MARCH1 has not been studied in the context of colorectal cancer. In this study, we demonstrated that MARCH1 is highly expressed in colorectal cancer tissues and cell lines. Furthermore, migration and invasion of colorectal tumor cells were inhibited via transfection with small interfering RNAs to suppress the expression of MARCH1. The western blot analysis showed that MARCH1 regulates epithelial–mesenchymal transition and the PI3K/AKT pathway. Moreover, 5‐fluorouracil inhibited the proliferation, migration, and invasion of tumor cells, via the targeting of MARCH1 and the consequent downregulation of the PI3K/AKT pathway, impacting the progression of epithelial–mesenchymal transition. In conclusion, our study shows that MARCH1 may play a role as an oncogene in colorectal cancer and may represent a new target molecule of 5‐fluorouracil.

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“…GOLIATH, like the other members of the PA domain-containing E3 ligase subfamily, exhibits a distinct domain architecture, consisting of a signal peptide, a PA domain, a TMD, and a RING (Really Interesting New Gene) domain (16). Ubiquitination events mediated by Drosophila Goliath family members have been shown to regulate specific cellular events such as endocytosis (13,17) and protein-protein interactions (18,19). Given the highly conserved structural architecture between GOLIATH and other PA-TM-RING proteins, we hypothesized that GOLIATH may play a role in the endocytic recycling of membrane receptors that regulate plasma cholesterol, such as LDLR.…”

Section: Introductionmentioning

confidence: 99%

GOLIATH regulates LDLR availability and plasma LDL cholesterol levels

Cheng

et al. 2020

Preprint

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Increasing the availability of hepatic low-density lipoprotein receptors (LDLR) remains a major clinical target for reducing circulating plasma LDL cholesterol (LDL-C) levels. Here, we identify the molecular mechanism underlying genome-wide significant associations in the GOLIATH locus with plasma LDL-C levels. We demonstrate that GOLIATH is an E3 ubiquitin ligase that ubiquitinates the LDL Receptor resulting in redistribution away from the plasma membrane. Overexpression of GOLIATH decreases hepatic LDLR and increases plasma LDL-C levels. Silencing of Goliath using antisense oligonucleotides, germline deletion, or AAV-CRISPR in vivo strategies increases hepatic LDLR abundance and availability, thus decreasing plasma LDL-C. In vitro ubiquitination assays demonstrate RING-dependent regulation of LDLR abundance at the plasma membrane. Our studies identify GOLIATH as a novel post-translational regulator of LDL-C levels via modulation of LDLR availability, which is likely important for understanding the complex regulation of hepatic LDLR.

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The Membrane-Associated MARCH E3 Ligase Family: Emerging Roles in Immune Regulation

Cited by 88 publications

References 129 publications

Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex

Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex

5‐FU inhibits migration and invasion of CRC cells through PI3K/AKT pathway regulated by MARCH1

GOLIATH regulates LDLR availability and plasma LDL cholesterol levels

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