NRAMPs: Versatile Transporters Involved in Metal Ion Homeostasis and Their Applications in Rice Breeding

doi:10.1016/j.rsci.2025.10.010

Abstract

Abstract:

The NRAMP (natural resistance-associated macrophage protein) family plays a pivotal role in metal ion transport, regulating both essential micronutrient uptake and toxic heavy metal accumulation in plants. In rice (Oryza sativa), OsNRAMP transporters critically influence metal homeostasis, stress adaptation, and grain safety. Among them, OsNRAMP5 serves as a major entry point for cadmium (Cd) and manganese (Mn) uptake, making it a prime target for low-Cd rice breeding. However, knockout of OsNRAMP5 leads to severe Mn deficiency, highlighting the need for precise genetic modifications (e.g., OsNRAMP5-Q337K), which reduce Cd accumulation while maintaining Mn nutrition. Additionally, OsNRAMP1 and OsNRAMP2 contribute to Cd translocation and plant immunity, whereas OsNRAMP3/4/6/7 participate in Mn, iron, and zinc distribution and stress responses. This review systematically summarizes the structural, functional, and regulatory mechanisms of OsNRAMPs, emphasizing their roles in metal transport, pathogen resistance, and abiotic stress adaptation. Furthermore, we discuss strategies for developing low-Cd rice varieties, including QTL-based breeding, CRISPR/Cas9-mediated gene editing, and multi-gene stacking approaches. Finally, we outline future research directions, such as structural engineering of metal-binding sites and field validation of engineered rice lines, to ensure sustainable rice production in heavy metal-contaminated soils.

Key words: NRAMP transporter, metal homeostasis, cadmium regulatory network, low-cadmium rice breeding

Huang Qina, Wu Lijuan, Jiang Hongrui, He Yan, Liu Song, Yang Changdeng, Liang Yan. NRAMPs: Versatile Transporters Involved in Metal Ion Homeostasis and Their Applications in Rice Breeding[J]. Rice Science, 2026, 33(1): 39-58.

Figures/Tables 5

Fig. 1. Phylogenetic relationships, gene structures, predicted phosphorylation sites, and promoter elements of OsNRAMP family. A, Evolutionary relationships among OsNRAMP transporters were inferred using the neighbor-joining method without distance correction (1 000 bootstrap replicates). Two sister groups were identified: one containing OsNRAMP1 and OsNRAMP5, and the other containing OsNRAMP2 and OsNRAMP7, both sharing a common ancestor. OsNRAMP3, OsNRAMP4, and OsNRAMP6 were found to share an ancestral lineage with OsNRAMP1 and OsNRAMP5. CDS, Coding sequence; UTR, Untranslated region. B, The highest predicted phosphorylation levels in OsNRAMP1, OsNRAMP5, and OsNRAMP6 occur between amino acid positions 251 and 350. In contrast, OsNRAMP2, OsNRAMP3, and OsNRAMP7 show peak phosphorylation within the first 100 amino acids (positions 1‒100 aa). C, Multiple functional cis-regulatory elements are present, including hormone-responsive motifs such as ABRE (abscisic acid), CGTCA/TGACG (methyl jasmonate), TCA-element (salicylic acid), GARE/P-box (gibberellic acid), and TGA-element (auxin). Stress-related elements include STRE (stress), WUN-motif (wound), LTR (cold), MYB/MYC (drought), and ARE (anaerobic induction).

Fig. 2. Haplotype analysis of OsNRAMP1‒7 across 3K Rice Genome (RG) panel. A, OsNRAMP1, a key gene involved in multi-ion transport, exhibits seven haplotypes in the 3K RG panel, showing extensive phenotypic variation. B, E, and F, OsNRAMP2, OsNRAMP5, and OsNRAMP6, which are involved in iron (Fe) and manganese (Mn) metabolism, each display six haplotypes. C, OsNRAMP3, which facilitates Mn2+ translocation, has five haplotypes, with 1 450 accessions carrying the OsNRAMP3-H001 haplotype. D and G, OsNRAMP4 and OsNRAMP7 each show eight haplotypes. NBH, Nucleotide-based haplotype; NAP, Number of accessions in the 3K RG panel. ‘-’ indicates a base deletion.

Table 1. Functional analysis of OsNRAMPs.

Protein	Subcellular localization	Spatiotemporal expression	Transport metal ion	Inducible expression^a	Suppressed expression^a	Function	Reference
OsNRAMP1	Plasma membrane	Mainly expressed in roots and leaves	Mn²⁺, Ni²⁺, Cd²⁺, Pb²⁺, etc.	-Fe, +Cd, +As, Infection of bacterial and fungal pathogens	JA, ABA, SA, BRs	Participate in regulation of basic resistance to pathogens, and maintain reactive oxygen species homeostasis	Takahashi
						Contribute to uptake and transport of Cd²⁺ and Mn²⁺, but not for Fe²⁺ or As³⁺	et al, 2011; Chang et al, 2020a; Chu
							et al, 2022
OsNRAMP2	Tonoplast	Mainly expressed in leaves	Cd²⁺, Fe²⁺	JA, ABA, ethephon, citric acid, high-Mn exposure, pathogen infection	SA	Transport iron from vacuole to	Li et al, 2021; Chang et al, 2022a; Yang et al, 2023
						cytoplasm
						Play a key role in seed germination
OsNRAMP3	Plasma membrane	Specifically expressed in vascular bundles	Mn²⁺, Cd²⁺, Ni²⁺	-Fe, ABA, fungal infection, citric acid	+Cd	Participate in Mn²⁺-influx	Yamaji et al, 2013; Yang
						Involve in Mn distribution and contribute to remobilization of Mn from old to young leaves	et al, 2013
						Act as a switch in response to
						environmental Mn availability
OsNRAMP4	Plasma membrane	Mainly expressed in roots	Al³⁺, Mn²⁺, Cd²⁺	+Al	/	Isolate Al³⁺ into vacuoles to remove Al toxicity	Xia et al, 2014;
						Transport Mn²⁺ from root to	Hao et al, 2022; Li S Z et al, 2023
						aboveground tissues
						Alter Cd accumulation in grains via
						affecting cellular Cd²⁺ distribution
OsNRAMP5	Plasma membrane	Constitutively expressed in mature roots, hulls, stems, and leaves	Mn²⁺, Fe²⁺ Pb²⁺, Cd²⁺, Co²⁺	-Fe, -Zn, high-Mn application, soil pH	+Cd	Involve in the absorption of external Mn²⁺, Cd²⁺, Co²⁺, and Fe²⁺	Ishimaru et al, 2012; Yang
						Responsible for uptake and transport of metal ions from roots to shoots	et al, 2014; Chang et al, 2020b; Huang et al, 2025
						Maintain ion homeostasis
OsNRAMP6	Plasma membrane	Specific expression in early-stage foliage	Fe²⁺, Mn²⁺, Cd²⁺	Fungal infection	/	As a transporter of Fe and Mn	Yang, 2014; Peris-Peris
						Negative regulation of rice immunity	et al, 2017
						Participate in Cd absorption and transport
OsNRAMP7	Plasma membrane	Root, node I, and spikelet at the flowering stage	Fe²⁺, Zn²⁺, Na⁺	-Fe, drought, salt, BRs, JA	CTK	Exhibit significant correlations with	Wu et al, 2021;
						Fe²⁺, Zn²⁺ distribution	Li J J et al, 2023
						Involve in Na⁺ transport and ABA-regulated drought tolerance pathway

Table 1. Functional analysis of OsNRAMPs.

Protein	Subcellular localization	Spatiotemporal expression	Transport metal ion	Inducible expression^a	Suppressed expression^a	Function	Reference
OsNRAMP1	Plasma membrane	Mainly expressed in roots and leaves	Mn²⁺, Ni²⁺, Cd²⁺, Pb²⁺, etc.	-Fe, +Cd, +As, Infection of bacterial and fungal pathogens	JA, ABA, SA, BRs	Participate in regulation of basic resistance to pathogens, and maintain reactive oxygen species homeostasis	Takahashi
						Contribute to uptake and transport of Cd²⁺ and Mn²⁺, but not for Fe²⁺ or As³⁺	et al, 2011; Chang et al, 2020a; Chu
							et al, 2022
OsNRAMP2	Tonoplast	Mainly expressed in leaves	Cd²⁺, Fe²⁺	JA, ABA, ethephon, citric acid, high-Mn exposure, pathogen infection	SA	Transport iron from vacuole to	Li et al, 2021; Chang et al, 2022a; Yang et al, 2023
						cytoplasm
						Play a key role in seed germination
OsNRAMP3	Plasma membrane	Specifically expressed in vascular bundles	Mn²⁺, Cd²⁺, Ni²⁺	-Fe, ABA, fungal infection, citric acid	+Cd	Participate in Mn²⁺-influx	Yamaji et al, 2013; Yang
						Involve in Mn distribution and contribute to remobilization of Mn from old to young leaves	et al, 2013
						Act as a switch in response to
						environmental Mn availability
OsNRAMP4	Plasma membrane	Mainly expressed in roots	Al³⁺, Mn²⁺, Cd²⁺	+Al	/	Isolate Al³⁺ into vacuoles to remove Al toxicity	Xia et al, 2014;
						Transport Mn²⁺ from root to	Hao et al, 2022; Li S Z et al, 2023
						aboveground tissues
						Alter Cd accumulation in grains via
						affecting cellular Cd²⁺ distribution
OsNRAMP5	Plasma membrane	Constitutively expressed in mature roots, hulls, stems, and leaves	Mn²⁺, Fe²⁺ Pb²⁺, Cd²⁺, Co²⁺	-Fe, -Zn, high-Mn application, soil pH	+Cd	Involve in the absorption of external Mn²⁺, Cd²⁺, Co²⁺, and Fe²⁺	Ishimaru et al, 2012; Yang
						Responsible for uptake and transport of metal ions from roots to shoots	et al, 2014; Chang et al, 2020b; Huang et al, 2025
						Maintain ion homeostasis
OsNRAMP6	Plasma membrane	Specific expression in early-stage foliage	Fe²⁺, Mn²⁺, Cd²⁺	Fungal infection	/	As a transporter of Fe and Mn	Yang, 2014; Peris-Peris
						Negative regulation of rice immunity	et al, 2017
						Participate in Cd absorption and transport
OsNRAMP7	Plasma membrane	Root, node I, and spikelet at the flowering stage	Fe²⁺, Zn²⁺, Na⁺	-Fe, drought, salt, BRs, JA	CTK	Exhibit significant correlations with	Wu et al, 2021;
						Fe²⁺, Zn²⁺ distribution	Li J J et al, 2023
						Involve in Na⁺ transport and ABA-regulated drought tolerance pathway

Fig. 3. Expression patterns of OsNRAMP family members and their functions in ion transport. OsNRAMP1, OsNRAMP2, OsNRAMP4, OsNRAMP5, and OsNRAMP7 are mainly expressed in rice roots, where they facilitate the uptake and transport of metal ions such as Mn2+, Fe2+, and Zn2+ from soil into the plant. OsNRAMP3, OsNRAMP5, and OsNRAMP7 are highly active in the stem, supporting the distribution of Mn, Fe, Zn, and Cd to various tissues. In leaves, OsNRAMP1, OsNRAMP2, OsNRAMP3, and OsNRAMP6 contribute to Mn distribution and (re)mobilization, with notably higher expression levels. Moreover, OsNRAMP2 and OsNRAMP5 are key transporters involved in Cd and Mn accumulation in grains. Notably, OsNRAMP5 plays a central role in reducing Cd toxicity and provides important insights for developing low-Cd rice varieties.

Fig. 4. Comparative regulatory networks of NRAMP transporters in plants and animals. A, Transcriptional regulation of NRAMPs. In plants (left), iron-responsive transcription factors (TFs) (FIT, BTS, bHLH101) and MYB TFs control NRAMP expression to balance metal uptake (Fe, Mn, Zn) and Cd detoxification. Interactions with other transporters (ZIP/IRT/HMA) further regulate metal homeostasis. In animals (right), pro-inflammatory signals (IFN-γ/LPS) activate myeloid-specific TFs (NF-κB, Pu.1, STAT1/3), inducing NRAMP1 (SLC11A1) expression and enhancing pathogen resistance. Basal expression is maintained by constitutive regulators (Sp1 and C/EBP). B, MicroRNA (miRNA)-mediated post-transcriptional control. In plants, Cd-induced miRNAs (e.g., osa-miR268, osa-miR7695) degrade OsNRAMP mRNAs or alter splicing, limiting Cd movement while preserving essential metals. In animals, immune-related miRNAs (e.g., miR-214) target a conserved sequence of NRAMPs, linking iron metabolism to antimicrobial defense. C, Post-translational modifications (PTMs). In plants, phosphorylation by WAKL4/CIPK23 modulates NRAMP stability and activity. In animals, MAPK-driven or Rsp5-Bsd2-mediated phosphorylation regulates NRAMP localization.

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