2022
DOI: 10.1016/j.molcel.2022.05.024
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Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability

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Cited by 20 publications
(12 citation statements)
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“…However, it is unclear which nutrients, if any, are constraining tumor growth. As shown in this work and reported by others 62,63 , the identification of growth advantages conferred by transporter overexpression pinpoints nutrients that are functionally limiting tumor growth. Using this approach, we found that A375 melanoma cells experience glucose and amino acid limitation in xenograft tumors.…”
Section: Discussionsupporting
confidence: 72%
“…However, it is unclear which nutrients, if any, are constraining tumor growth. As shown in this work and reported by others 62,63 , the identification of growth advantages conferred by transporter overexpression pinpoints nutrients that are functionally limiting tumor growth. Using this approach, we found that A375 melanoma cells experience glucose and amino acid limitation in xenograft tumors.…”
Section: Discussionsupporting
confidence: 72%
“…Notably, the expression pattern of OAT-3 is similar to that for iron staining in which FT NPs were also predominantly observed in the liver parenchyma. A recent work mentioned that some SLC family members (e.g., SLCO2B1) play a role in the uptake of non-transferrin bound iron . Taken together, these results suggest that the SLC family could play a role in FT uptake.…”
Section: Resultsmentioning
confidence: 64%
“…A recent work mentioned that some SLC family members (e.g., SLCO2B1) play a role in the uptake of non-transferrin bound iron. 29 Taken together, these results suggest that the SLC family could play a role in FT uptake.…”
Section: ■ Results and Discussionmentioning
confidence: 78%
“…Comparing the proteome of HEK293 cells treated with 400 μM of fluidizing oleic acid versus 400 μM of rigidifying palmitic acid shows that ADI-POR2 is one of the most strikingly regulated proteins, being elevated in the presence of palmitic acid because of reduced interaction with, and ubiquitination by, the ER-resident ubiquitin ligase RNF145. [61] Separately, ADIPOR2 emerged as one of the top hits in three unbiased CRISPR/Cas9 screens in human cells designed to identify genes essential for the response to membrane-rigidifying challenges: one screen identified ADIPOR2 mutants as intolerant of palmitic acid and other SFAs, [62] another screen identified ADIPOR2 overexpression as a potent mechanism to increase resistance to palmitic acid, [63] and a third identified ADIPOR2 as essential to combat hypoxia-induced desaturase inhibition. [11] siRNA silencing of ADIPOR2 in the presence of 200 μM palmitic acid, of which the plasma concentration is often >1 mM, [64] results in excess SFA content in phospholipids and membrane rigidification in all mammalian cell types examined so far: HEK293 (embryonic kidney-derived), [65] HepG2 (hepatocyte-derived), [65] 131N1 (astrocyte-like), [65] INS-1E (rat beta cell-derived), [66] Jurkat E6-1 (T lymphocyte-derived), [66] U2 O-S (bone sarcoma-derived), [66] and 2) by homology with the C. elegans PAQR-2, ADIPOR2 may multimerize with an activator ("X" in the model) in a membrane rigidity-dependent manner; (3) once activated, the ADIPOR2-intrinsic ceramidase hydrolyzes ceramides, producing sphingosine that, once phosphorylated, becomes sphingosine 1-phosphate (S1P), a signaling molecule; (4) S1P is secreted then bind to the S1P receptor S1PR3, a GPCR that signals to activate SREBPs; (5) separately, S1P acts as an intracellular ligand for PPARγ; (6) the SREBPs and PPARγ promote transcription of the Δ9 desaturase SCD and other genes, contributing to the conversion of dietary SFAs to UFAs; (7) an ER-associated fatty acid elongation complex (the interaction with HACD3 is thoroughly verified while the interaction with HSD17B12 and ELOVL3/6 is less solidly established) and ACSL4 are recruited by ADIPOR2, allowing local production of long-chain PUFAs (LCPUFAs) and their channelling toward incorporation into phospholipids; (8) once membrane fluidity is restored, RNF145 is stabilized and ubiquitinates ADIPOR2 that is then degraded; and (9) fluidizing lipids are shared among cells and tissues such that membrane homeostasis is cell non-autonomous.…”
Section: Paqrs In M Musculus and H Sapiensmentioning
confidence: 99%
“…Comparing the proteome of HEK293 cells treated with 400 μM of fluidizing oleic acid versus 400 μM of rigidifying palmitic acid shows that ADIPOR2 is one of the most strikingly regulated proteins, being elevated in the presence of palmitic acid because of reduced interaction with, and ubiquitination by, the ER‐resident ubiquitin ligase RNF145. [ 61 ] Separately, ADIPOR2 emerged as one of the top hits in three unbiased CRISPR/Cas9 screens in human cells designed to identify genes essential for the response to membrane‐rigidifying challenges: one screen identified ADIPOR2 mutants as intolerant of palmitic acid and other SFAs, [ 62 ] another screen identified ADIPOR2 overexpression as a potent mechanism to increase resistance to palmitic acid, [ 63 ] and a third identified ADIPOR2 as essential to combat hypoxia‐induced desaturase inhibition. [ 11 ]…”
Section: Paqr Proteins and Membrane Homeostasismentioning
confidence: 99%