Cellular uptake of vitamin B12: Role and fate of TCblR/CD320, the transcobalamin receptor

Gick, Gregory; Arora, Kaveri; Sequeira, Jeffrey M.; Nakayama, Yasumi; Lai, Shao-Chiang; Quadros, Edward V.

doi:10.1016/j.yexcr.2020.112256

Cited by 23 publications

(26 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Relevantly, mammalian CD320 receptors are highly upregulated on the surface of tumor cells and metabolically active cells to meet the high demand for Cbl, especially for the purposes of nucleotide synthesis (41,42). They are also upregulated in certain phases of the cell cycle (43,44). The CD320 enrichment in tumors is so strong and specific that it has been exploited to visualize tumors using labeled Cbl derivatives (see reference 45 and references therein) and to target tumors for therapy with administration of toxic analogs (46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

The Avian Retroviral Receptor Tva Mediates the Uptake of Transcobalamin Bound Vitamin B ₁₂ (Cobalamin)

Krchlíková

Mikešová

Geryk

et al. 2021

J Virol

View full text Add to dashboard Cite

The Avian sarcoma and leukosis viruses (ASLVs) are important chicken pathogens. Some of the virus subgroups, including ASLV-A and K, utilize the Tva receptor for cell entrance. Though Tva was identified three decades ago, its physiological function remains unknown. Previously, we have noted an intriguing resemblance and orthology between the chicken gene coding for Tva and the human gene coding for CD320, a receptor involved in cellular uptake of transcobalamin (TC) in complex with vitamin B12/cobalamin (Cbl). Here we show that both the transmembrane and the glycosylphosphatidylinositol (GPI)-anchored form of Tva in the chicken cell line DF-1 promotes the uptake of Cbl with help of expressed and purified chicken TC. The uptake of TC-Cbl complex was monitored using an isotope- or fluorophore-labeled Cbl. We show that (i) TC-Cbl is internalized in chicken cells; and (ii) the uptake is lower in the Tva-knockout cells and higher in Tva-overexpressing cells when compared with wild type chicken cells. The relation between physiological function of Tva and its role in infection was elaborated by showing that infection with ASLV subgroups (targeting Tva) impairs the uptake of TC-Cbl, while this is not the case for cells infected with ASLV-B (not recognized by Tva). In addition, exposure of the cells to a high concentration of TC-Cbl alleviates the infection with Tva-dependent ASLV. IMPORTANCE: We demonstrate that the ASLV receptor Tva participates in the physiological uptake of TC-Cbl, because the viral infection suppresses the uptake of Cbl and vice versa. Our results pave the road for future studies addressing the issues: (i) whether a virus infection can be inhibited by TC-Cbl complexes in vivo; and (ii) whether any human virus employs the human TC-Cbl receptor CD320. In broader terms, our study sheds light on the intricate interplay between physiological roles of cellular receptors and their involvement in virus infection.

show abstract

Section: Discussionmentioning

confidence: 99%

The Avian Retroviral Receptor Tva Mediates the Uptake of Transcobalamin Bound Vitamin B ₁₂ (Cobalamin)

Krchlíková

Mikešová

Geryk

et al. 2021

J Virol

View full text Add to dashboard Cite

show abstract

“…Następnie endosomy zawierające kompleks holoTC-TCII-R łączą się z lizosomami. Pod wpływem enzymów lizosomalnych dochodzi do degradacji kompleksu i uwolnienia Cbl do cytoplazmy [7,11,13,15]. Gick i wsp.…”

Section: źRódło Biologicznie Aktywnych Postaci Witaminy B 12 W Ustrojuunclassified

“…Gick i wsp. [15] wykazali, że receptory TCII-R nie mogą być ponownie wbudowywane w błonę komórkową, a wychwyt Cbl jest uzależniony od syntezy de novo cząsteczek tego receptora w komórce. Poziom ekspresji receptora holoTC jest zależny od fazy cyklu komórkowego.…”

Section: źRódło Biologicznie Aktywnych Postaci Witaminy B 12 W Ustrojuunclassified

See 1 more Smart Citation

Kobalamina – właściwości biomedyczne i niedobór w ujęciu biochemicznym

Rzepka

Słaby

Wrześniok

2021

Postępy Higieny I Medycyny Doświadczalnej

View full text Add to dashboard Cite

Abstrakt Kobalamina (witamina B12) jest rozpuszczalnym w wodzie związkiem organicznym, zaliczanym do witamin grupy B. Złożona budowa i polarność cząsteczki witaminy B12 sprawiają, że do jej prawidłowego wykorzystania i przemian w organizmie człowieka niezbędny jest udział wyspecjalizowanych białek. Głównym źródłem kobalaminy człowieka jest pokarm pochodzenia zwierzęcego. Ze względu na rezerwy tkankowe tej witaminy, jej niedobór ujawnia się dopiero po kilku latach niewystarczającej podaży z pożywieniem. Badania przesiewowe pod kątem deficytu kobalaminy są jednak uzasadnione u osób z czynnikami ryzyka hipokobalaminemii, takimi jak: stan po resekcji żołądka lub jelita cienkiego, dieta wegańska, długotrwałe stosowanie metforminy, antagonistów receptora histaminowego H2 oraz leków z grupy inhibitorów pompy protonowej, a także podeszły wiek. Witamina B12 jako kofaktor enzymatyczny uczestniczy w licznych przemianach wewnątrzmitochondrialnych oraz w syntezie metioniny, niezbędnej do powstania S-adenozylometioniny istotnej w procesie metylacji cząsteczek biologicznie czynnych. Przez powiązania metaboliczne z kwasem foliowym kobalamina wpływa na proces syntezy DNA i podział komórki. Obecnie coraz częściej zwraca się uwagę na potencjalny udział niedoboru witaminy B12 w patogenezie chorób neurodegeneracyjnych, a także nowotworowych. Niedobór kobalaminy na poziomie molekularnym destabilizuje genom komórek, zwiększając ryzyko ich złośliwej transformacji. Jednak u osób z chorobą nowotworową lub obciążonych ryzykiem jej rozwoju witamina B12 może nasilać ekspansję komórek neoplastycznych.

show abstract

“…Because vitamin B12 is a cofactor of enzymes involved in recycling of folates for DNA synthesis (5), the need for B12 is elevated in highly proliferating cells such as pluripotent cancer cells (4). This correlates with the overexpression of the CD320 protein, the cellular receptor (TCblR, sometimes called CD320) of transcobalamin-B12 complex (4,6). Targeting the cellular uptake route for vitamin B12 for potential cancer diagnosis or therapy has been described in previous studies (5), where strategies included the derivatization of vitamin B12 (7) or the coupling of a receptor binding antibody to saporin (8,9).…”

Section: Introductionmentioning

confidence: 99%

Generation of nanobodies targeting the human, transcobalamin-mediated vitamin B₁₂ uptake route

Bloch

Sequeira

Ramírez

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Cellular uptake of vitamin B12 in humans is mediated by the endocytosis of the B12 carrier protein transcobalamin (TC) via its cognate cell surface receptor TCblR (or CD320), encoded by the CD320 gene. Because CD320 expression is associated with the cell cycle and upregulated in highly proliferating cells such as cancer cells, this uptake route is a potential target for cancer therapy. We developed and characterized four camelid nanobodies that bind TC or the interface of the TC:TCblR complex with nanomolar affinities. We determined X-ray crystal structures of all four nanobodies in complex with TC:TCblR, which enabled us to map their binding sites. When conjugated to a toxin, three of these nanobodies are capable of inhibiting the growth of HEK293T cells and therefore have the potential to inhibit the growth of human cancer cells. We visualized the cellular binding and endocytic uptake of the most potent nanobody (TCNB4) using fluorescent light microscopy. The co-crystal structures of TC:TCblR with another nanobody (TCNB34) revealed novel features of the interface of TC and the LDLR-A1 domain of TCblR. Our findings rationalize the structural basis for a decrease in affinity of TC-B12 binding caused by the TCblR-Glu88 deletion mutant.

show abstract

Cellular uptake of vitamin B12: Role and fate of TCblR/CD320, the transcobalamin receptor

Cited by 23 publications

References 28 publications

The Avian Retroviral Receptor Tva Mediates the Uptake of Transcobalamin Bound Vitamin B ₁₂ (Cobalamin)

The Avian Retroviral Receptor Tva Mediates the Uptake of Transcobalamin Bound Vitamin B ₁₂ (Cobalamin)

Kobalamina – właściwości biomedyczne i niedobór w ujęciu biochemicznym

Generation of nanobodies targeting the human, transcobalamin-mediated vitamin B₁₂ uptake route

Contact Info

Product

Resources

About

Cellular uptake of vitamin B12: Role and fate of TCblR/CD320, the transcobalamin receptor

Cited by 23 publications

References 28 publications

The Avian Retroviral Receptor Tva Mediates the Uptake of Transcobalamin Bound Vitamin B 12 (Cobalamin)

The Avian Retroviral Receptor Tva Mediates the Uptake of Transcobalamin Bound Vitamin B 12 (Cobalamin)

Kobalamina – właściwości biomedyczne i niedobór w ujęciu biochemicznym

Generation of nanobodies targeting the human, transcobalamin-mediated vitamin B12 uptake route

Contact Info

Product

Resources

About

The Avian Retroviral Receptor Tva Mediates the Uptake of Transcobalamin Bound Vitamin B ₁₂ (Cobalamin)

The Avian Retroviral Receptor Tva Mediates the Uptake of Transcobalamin Bound Vitamin B ₁₂ (Cobalamin)

Generation of nanobodies targeting the human, transcobalamin-mediated vitamin B₁₂ uptake route