Ubiquitin-like protein MNSFβ covalently binds to cytosolic 10-formyltetrahydrofolate dehydrogenase and regulates thymocyte function

Nakamura, Morihiko; Watanabe, Natsuko; Notsu, Kaori

doi:10.1016/j.bbrc.2015.07.083

Cited by 7 publications

(6 citation statements)

References 27 publications

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“…Of note, computational prediction of ubiquitination sites using several online tools indicated presence of numerous potential ubiquitination sites which overlap in mouse and human ALDH1L1. Interestingly, ALDH1L1 is a target for modification by the ubiquitin-like modifier MNSF-ß, which attaches at Lys72 [ 55 ]. While the function of this modification is not clear, it may regulate apoptosis in thymocytes [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

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CHIP E3 ligase mediates proteasomal degradation of the proliferation regulatory protein ALDH1L1 during the transition of NIH3T3 fibroblasts from G0/G1 to S-phase

et al. 2018

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ALDH1L1 is a folate-metabolizing enzyme abundant in liver and several other tissues. In human cancers and cell lines derived from malignant tumors, the ALDH1L1 gene is commonly silenced through the promoter methylation. It was suggested that ALDH1L1 limits proliferation capacity of the cell and thus functions as putative tumor suppressor. In contrast to cancer cells, mouse cell lines NIH3T3 and AML12 do express the ALDH1L1 protein. In the present study, we show that the levels of ALDH1L1 in these cell lines fluctuate throughout the cell cycle. During S-phase, ALDH1L1 is markedly down regulated at the protein level. As the cell cultures become confluent and cells experience increased contact inhibition, ALDH1L1 accumulates in the cells. In agreement with this finding, NIH3T3 cells arrested in G1/S-phase by a thymidine block completely lose the ALDH1L1 protein. Treatment with the proteasome inhibitor MG-132 prevents such loss in proliferating NIH3T3 cells, suggesting the proteasomal degradation of the ALDH1L1 protein. The co-localization of ALDH1L1 with proteasomes, demonstrated by confocal microscopy, supports this mechanism. We further show that ALDH1L1 interacts with the chaperone-dependent E3 ligase CHIP, which plays a key role in the ALDH1L1 ubiquitination and degradation. In NIH3T3 cells, silencing of CHIP by siRNA halts, while transient expression of CHIP promotes, the ALDH1L1 loss. The downregulation of ALDH1L1 is associated with the accumulation of the ALDH1L1 substrate 10-formyltetrahydrofolate, which is required for de novo purine biosynthesis, a key pathway activated in S-phase. Overall, our data indicate that CHIP-mediated proteasomal degradation of ALDH1L1 facilitates cellular proliferation.

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Section: Discussionmentioning

confidence: 99%

“…Interestingly, ALDH1L1 is a target for modification by the ubiquitin-like modifier MNSF-ß, which attaches at Lys72 [ 55 ]. While the function of this modification is not clear, it may regulate apoptosis in thymocytes [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

CHIP E3 ligase mediates proteasomal degradation of the proliferation regulatory protein ALDH1L1 during the transition of NIH3T3 fibroblasts from G0/G1 to S-phase

et al. 2018

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“…Previous evidences have shown that MNSFβ can covalently attach to specific target proteins with a linkage between the C‐terminal G74 and certain lysines, such as K110 in Bcl‐G, K294 in endophilin II, K481 in heat shock protein 60 (HSP60) and K72 in formate dehydrogenase (FDH). 30 , 33 , 34 , 35 K139 in IGF2BP2 has been the predominant site for its ubiquitination. 36 We thus assume that the covalent binding between G74 in MNSFβ with K139 in IGF2BP2 may be the recognition site to protect the degradation of IGF2BP2.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is notable that among the candidates that potentially bind to MNSFβ, ribosomal protein S3A (RPS3A) was reported to promote the biological processes related to tumourigenesis, metastasis and immunosuppression in hepatocellular carcinoma patients, 31 in formate dehydrogenase (FDH). 30,[33][34][35] K139 in IGF2BP2 has been the predominant site for its ubiquitination. 36 We thus assume that the covalent binding between G74 in MNSFβ with K139 in IGF2BP2 may be the recognition site to protect the degradation of IGF2BP2.…”

Section: The Appropriate Trophoblast Differentiation Towards Invasivementioning

confidence: 99%

MNSFβ regulates placental development by conjugating IGF2BP2 to enhance trophoblast cell invasiveness

Yang

Liu

et al. 2021

Cell Proliferation

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“…One well-characterized MNSFβ target is BCL-G, a proapoptotic member of the BCL-2 family, that was shown to regulate the extracellular signal-regulated kinase (ERK)/ mitogen-activated protein kinase (MAPK) signal cascade in mouse macrophage (Raw264.7) cells lines (11). Given the important roles of MNSFβ proteins, it has been studied extensively in human and mouse models (5,12). However, porcine models may better serve the scientific research community because, compared to mice, they are more similar to humans in both physiology and anatomy (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Porcine ubiquitin-like protein MNSFβ promotes cell apoptosis and covalently binds to BCL-G to enhance staurosporine-induced apoptosis

Chen¹,

Wang²,

Wang³

et al. 2020

Ann Transl Med

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Background: Monoclonal non-specific suppressor factor β (MNSFβ) is a ubiquitously expressed member of the ubiquitin-like family. It functions as a regulator of cell apoptosis and a potential tumor suppressor, playing a vital role in the processes of immune cell function and apoptosis.Methods: The present study constructed GFP-pMNSFβ swine umbilical vein endothelial cell (SUVEC) lines and investigated the function of porcine MNSFβ (pMNSFβ) in apoptosis, as well as its interactions with pBCL-G. Results revealed that stably expressed pMNSFβ protein in SUVEC lines significantly enhanced staurosporine (STS)-induced apoptosis. pMNSFβ proteins interacted with pBCL-G proteins and the expression of these interacting proteins synergized to further enhance STS-induced apoptosis.Results: GFP-pMNSFβ stably expressed SUVEC lines through transient transfection and neomycin screening methods. Over 90% of the SUVEC cultures expressed GFP signals, and 41.5 kDa GFP-pMNSFβ proteins were detected with western blotting methods. Annexin V-PE/PI staining and flow cytometry analyses showed that overexpression of pMNSFβ proteins significantly elevated STS-induced apoptosis rates. Co-immunoprecipitation methods revealed an interaction between pMNSFβ and pBCL-G proteins. BCL-G is a proapoptotic member of the BCL-2 family that has been shown to be misexpressed in human systemic lupus erythematosus, as well as mammary and prostate cancers. Here, we demonstrated that the co-expression and potential conjugation of pMNSFβ and pBCL-G proteins synergistically enhanced STSinduced apoptosis.Conclusions: The present study was the first to characterize the function of MNSFβ in porcine cells, and to clarify the function of MNSFβ in apoptosis. These results reveal that pMNSFβ is a potential molecular model for future investigations of diseases related to human MNSFβ dysfunction.

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Ubiquitin-like protein MNSFβ covalently binds to cytosolic 10-formyltetrahydrofolate dehydrogenase and regulates thymocyte function

Cited by 7 publications

References 27 publications

CHIP E3 ligase mediates proteasomal degradation of the proliferation regulatory protein ALDH1L1 during the transition of NIH3T3 fibroblasts from G0/G1 to S-phase

CHIP E3 ligase mediates proteasomal degradation of the proliferation regulatory protein ALDH1L1 during the transition of NIH3T3 fibroblasts from G0/G1 to S-phase

MNSFβ regulates placental development by conjugating IGF2BP2 to enhance trophoblast cell invasiveness

Porcine ubiquitin-like protein MNSFβ promotes cell apoptosis and covalently binds to BCL-G to enhance staurosporine-induced apoptosis

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