Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Yamamotoya, Takeshi; Nakatsu, Yusuke; Kushiyama, Akifumi; Matsunaga, Yasuka; Ueda, Koji; Inoue, Yuki; Inoue, Masakí; Sakoda, Hideyuki; Fujishiro, Midori; Ono, Hiraku; Kanazawa, Hiroshi; Ishihara, Hideharu; Asano, Tomohiko

doi:10.1038/s41598-017-13432-x

Cited by 15 publications

(16 citation statements)

References 36 publications

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“…We are unclear of whether TFG’s effects on ERGIC are involved; however, what we demonstrated is more non-housekeeping, rather a specific effect on FANCD2-V2. This is consistent with TFG’s role in promoting the pancreatic β cell mass [ 24 ]. We think both cases are a specific aspect of TFG’s function, mostly independent of ERGIC.…”

Section: Discussionsupporting

confidence: 85%

TFG-maintaining stability of overlooked FANCD2 confers early DNA-damage response

Hokutan

Shen

et al. 2020

aging

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Emerging Fanconi Anemia (FA) signaling in the field of cancer research annotates the extreme importance of its center player, Fanconi Anemia complementation group D2 (FANCD2) in protecting human cells from going awry. However, a previously-unrecognized form of FANCD2, namely FANCD2-V2, is understudied. We report TRK-Fused Gene (TFG) is critical for roles played by FANCD2-V2 in early responses to DNA damage, but not for FANCD2-V1, the long-known form of FANCD2. FANCD2-V2 forms nuclear foci upon DNA damage, and both its focus appearance and disappearance are earlier than FANCD2-V1. The amino acid/aa 5-100 of TFG and the aa1437-1442 of FANCD2-V2 were identified to contribute to their interaction, which maintains the steady-state level of FANCD2-V2 protein. TFGΔaa5-100 or FANCD2-V2Δaa1437-1442-carrying cells could not show timely focus formation of FANCD2-V2 upon DNA damage and gained carcinogenicity over time. This study provides a previously-unknown key to unlock in-depth insights into maintaining genome stability, fostering translational studies on preventing, diagnosing and/or treating related diseases.

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Section: Discussionsupporting

confidence: 85%

TFG-maintaining stability of overlooked FANCD2 confers early DNA-damage response

Hokutan

Shen

et al. 2020

aging

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“…Recently many interesting observations are accumulating about the role of TFG protein, which belongs to the coat protein complex II transportation system from the endoplasmic reticulum (ER) to the ER-Golgi intermediate compartment (ERGIC), and plays a very important role in maintaining the efficacy of the vesicles (12), in various areas of basic cellular biology Dysphagia and breathing disorders begin to increase after the patients' 50s. (13), insulin metabolism (14), and in a discussion of future cancer therapy (15). It is very important with this background to shed lights on the detailed clinical facts and the natural history in patients with HMSN-P.…”

Section: Discussionmentioning

confidence: 99%

The natural history of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) in 97 Japanese patients

Fujisaki

Suwazono

Suehara

et al. 2018

IRDR

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Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is a motor and sensory neuronopathy with autosomal dominant inheritance, adult onset, slowly progressive course, and is associated with (TFG) mutation. At advanced stages, respiratory failure and dysphagia becomes life-threatoning, and patients typically die by their 70s. Although there is currently no evidence for effective treatment, a therapy may be found by elucidation of the function of TFG. Recently its pathomechanism has been proposed to be associated with abnormalities in protein transfer from the endoplasmic reticulum. Such pathomechanisms might involve a similar process in amyotrophic lateral sclerosis; thus, its pathomechanisms and treatment strategy might make it a good model for neurodegenerative disorders. It is of great value to clarify the natural history of HMSN-P, in oder to judge the treatment effect. By evaluating 97 patients (79 out of 97 were examined and all confirmed with p.Pro 285 Leu mutation) in this study, it was confirmed that this disease follows a uniform course in the earlier stages, and there are individual differences in the onset between 20 and 30 years. Such uniformity might be due to the proposed single gene abnormality. At advanced stages, there are larger individual differences in the progression, but the reasons for these are unknown. Longer survival might be achieved with a better care for respiratory failure and dysphagia if such cares were undertaken at appropriate times.

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“…In other cell systems, TFG has been described as a negative regulator of the UPS, and its overexpression can lead to increased ER stress by interfering with ERAD [53]. Additionally, some non-immune secretory cells like insulin-producing β-cells [54] or sebocytes [55] also depend on TFG. While the functions of TFG may vary in different cell types and may depend on its abundance, all published data point to a function of TFG in homeostasis of the ER and the secretory pathway.…”

Section: Introductionmentioning

confidence: 99%

TFG is required for autophagy flux and to prevent endoplasmic reticulum stress in CH12 B lymphoma cells

Steinmetz

Schlötzer‐Schrehardt²,

Hearne

et al. 2020

Autophagy

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Plasma cells depend on quality control of newly synthesized antibodies in the endoplasmic reticulum (ER) via macroautophagy/autophagy and proteasomal degradation. The cytosolic adaptor protein TFG (Trkfused gene) regulates ER-Golgi transport, the secretory pathway and proteasome activity in non-immune cells. We show here that TFG is upregulated during lipopolysaccharide-and CpG-induced differentiation of B1 and B2 B cells into plasmablasts, with the highest expression of TFG in mature plasma cells. CRISPR-CAS9-mediated gene disruption of tfg in the B lymphoma cell line CH12 revealed increased apoptosis, which was reverted by BCL2 but even more by ectopic TFG expression. Loss of TFG disrupted ER structure, leading to an expanded ER and increased expression of ER stress genes. When compared to wild-type CH12 cells, tfg KO CH12 cells were more sensitive toward ER stress induced by tunicamycin, monensin and proteasome inhibition or by expression of an ER-bound immunoglobulin (Ig) μ heavy (µH) chain. CH12 tfg KO B cells displayed more total LC3, lower LC3-II turnover and increased numbers and size of autophagosomes. Tandem-fluorescent-LC3 revealed less accumulation of GFP-LC3 in starved and chloroquine-treated CH12 tfg KO B cells. The GFP:RFP ratio of tandem-fluorescent-LC3 was higher in tunicamycin-treated CH12 tfg KO B cells, suggesting less autophagy flux during induced ER stress. Based on these data, we suggest that TFG controls autophagy flux in CH12 B cells and propose that TFG is a survival factor that alleviates ER stress through the support of autophagy flux in activated B cells and mature plasma cells.

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Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Cited by 15 publications

References 36 publications

TFG-maintaining stability of overlooked FANCD2 confers early DNA-damage response

TFG-maintaining stability of overlooked FANCD2 confers early DNA-damage response

The natural history of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) in 97 Japanese patients

TFG is required for autophagy flux and to prevent endoplasmic reticulum stress in CH12 B lymphoma cells

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