Identification of human genes of iron homeostasis

铁是必不可少的，但也是高度化学反应性和潜在毒性的。细胞安全地使用铁元素的机制尚不清楚；铁管理缺陷是细胞死亡途径中称为铁下垂的一个致病因素。聚rC结合蛋白1 （polyrc binding protein 1, PCBP1）是一种多功能蛋白，在哺乳动物细胞中作为细胞质铁伴侣，结合铁并将铁传递给受体蛋白。虽然PCBP1在细胞中分配铁，但其在哺乳动物组织中管理铁的作用仍未被探索。肝脏是铁摄取、利用、储存和分泌的高度专门化器官。肝细胞缺乏PCBP1的小鼠表现出肝铁稳态缺陷，肝铁水平低，铁酶活性降低，细胞自主铁调节系统调节失调。这些小鼠自发发展为肝脏疾病，包括肝脂肪变性、炎症和变性。转录组分析表明脂质生物合成和氧化应激反应途径被激活，包括抗铁致下沉介质Gpx4。虽然pcbp1缺失的肝脏缺铁，但膳食补铁并不能预防脂肪变性；相反，饮食铁限制和维生素E抗氧化治疗可以预防肝脏疾病。pcbp1缺失的肝细胞表现出增加的不稳定铁和活性氧的产生，对铁和促氧化剂过敏，并且由于无伴侣铁的反应性而积累氧化损伤的脂质。结论：pcbp1缺失小鼠肝细胞中的无伴侣铁可导致活性氧的产生，在没有铁过载的情况下导致脂质过氧化和脂肪变性。因此，PCBP1的铁伴侣活性对于限制胞质铁的毒性至关重要，并且可能是防止触发铁致细胞死亡途径的脂质过氧化的关键因素。

1) Iron is essential yet also highly chemically reactive and potentially toxic. The mechanisms that allow cells to use iron safely are not clear; defects in iron management are a causative factor in the cell death pathway known as ferroptosis. Poly rC binding protein 1 (PCBP1) is a multifunctional protein that serves as a cytosolic iron chaperone, binding and transferring iron to recipient proteins in mammalian cells. While PCBP1 distributes iron in cells, its role in managing iron in mammalian tissues remains unexplored. The liver is highly specialized for iron uptake, utilization, storage, and secretion. Mice lacking PCBP1 in hepatocytes exhibited defects in liver iron homeostasis with low levels of liver iron, reduced activity of iron enzymes, and misregulation of the cell-autonomous iron regulatory system. These mice spontaneously developed liver disease with hepatic steatosis, inflammation, and degeneration. Transcriptome analysis indicated activation of lipid biosynthetic and oxidative stress response pathways, including the anti-ferroptotic mediator Gpx4. Although PCBP1-deleted livers were iron-deficient, dietary iron supplementation did not prevent steatosis; instead, dietary iron restriction and antioxidant therapy with vitamin E prevented liver disease. PCBP1-deleted hepatocytes exhibited increased labile iron and production of reactive oxygen species, were hypersensitive to iron and prooxidants, and accumulated oxidatively-damaged lipids due to the reactivity of unchaperoned iron. Conclusions: Unchaperoned iron in PCBP1-deleted mouse hepatocytes leads to production of reactive oxygen species, resulting in lipid peroxidation and steatosis in the absence of iron overload. The iron chaperone activity of PCBP1 is therefore critical for limiting the toxicity of cytosolic iron and may be a key factor in preventing the lipid peroxidation that triggers the ferroptotic cell death pathway. 2) Iron-containing proteins rely on the incorporation of a set of iron cofactors for activity. The cofactors must be synthesized or assembled from raw materials located within the cell. The chemical nature of this pool of raw material - referred to as the labile iron pool has become clearer with the identification of micro- and macro-molecules that coordinate iron within the cell. These molecules function as a buffer system for the management of intracellular iron and are the focus of this review, with emphasis on the major iron chaperone protein coordinating the labile iron pool: poly C-binding protein 1. 3) Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Here, we identify the RNA binding protein, poly(C)-binding protein 1 (PCBP1) as an intracellular immune checkpoint that is up-regulated in activated T cells to prevent conversion of effector T (Teff) cells into regulatory T (Treg) cells, by restricting the expression of Teff cell-intrinsic Treg commitment programs. This was critical for stabilizing Teff cell functions and subverting immune-suppressive signals. T cell-specific deletion of Pcbp1 favored Treg cell differentiation, enlisted multiple inhibitory immune checkpoint molecules including PD-1, TIGIT, and VISTA on tumor-infiltrating lymphocytes, and blunted antitumor immunity. Our results demonstrate a critical role for PCBP1 as an intracellular immune checkpoint for maintaining Teff cell functions in cancer immunity. 4)Post-transcriptional regulation of cytokine production is crucial to ensure appropriate immune responses. We previously demonstrated that poly-rC-binding protein-1 (PCBP1) can act as a trans-acting factor to stabilize transcripts encoding sortilin, which mediates cytokine trafficking. Here, we report that PCBP2, which strongly resembles PCBP1, can stabilize sortilin transcripts in macrophages using the same mechanism employed by PCBP1. PCBP2 recognized the C-rich element in the 3' UTR of sortilin mRNA, and PCBP2 knockdown decreased sortilin transcripts, indicating that PCBP2 stabilizes sortilin mRNA by binding to its 3' UTR. Zn2+ reversibly inhibited the nucleotide binding ability of PCBP2 in vitro. These findings suggest that both PCBP2 and PCBP1 may control the stability of sortilin transcripts by sensing intracellular Zn2+ levels in immune cells. 5) Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e-7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency. 6) Redox balance is essential for normal brain, hence dis-coordinated oxidative reactions leading to neuronal death, including programs of regulated death, are commonly viewed as an inevitable pathogenic penalty for acute neuro-injury and neurodegenerative diseases. Ferroptosis is one of these programs triggered by dyshomeostasis of three metabolic pillars: iron, thiols, and polyunsaturated phospholipids. This review focuses on: (1) lipid peroxidation (LPO) as the major instrument of cell demise, (2) iron as its catalytic mechanism, and (3) thiols as regulators of pro-ferroptotic signals, hydroperoxy lipids. Given the central role of LPO, we discuss the engagement of selective and specific enzymatic pathways versus random free radical chemical reactions in the context of the phospholipid substrates, their biosynthesis, intracellular location, and related oxygenating machinery as participants in ferroptotic cascades. These concepts are discussed in the light of emerging neuro-therapeutic approaches controlling intracellular production of pro-ferroptotic phospholipid signals and their non-cell-autonomous spreading, leading to ferroptosis-associated necroinflammation.