The AF-2 domain of estrogen-related receptor interacts with PPRC1 to modulate larval epidermal marking in Bombyx mori
- 1Integrative Science Center of Germplasm Creation in Western China (Chongqing) Science City, Biological Science Research Center, Southwest University, Chongqing, China
Abstract
Estrogen-related receptors (ERRs) have no natural ligands, vertebrate ERRs rely on their activation function-2 (AF-2) structural domain to recruit coactivators for transcriptional regulation. While metabolic regulation in insects differs significantly from that in vertebrates, it remains unclear whether the regulatory function of insect ERR requires coactivators. Using silkworms as the research subject, this study aims to analyze the molecular mechanisms of ERR-regulated metabolism in insects and refine the metabolic regulatory network. This study applied CRISPR/Cas9 gene editing technology to knock out the AF-2 domain of BmERR in the lepidopteran silkworms and examined its effects on functional role, associated interacting factors, and related physiological processes. Disruption of the BmERR AF-2 domain inhibited the expression of melanin metabolism-related genes BmTH, BmDDC, BmAA-NAT, Bmebony, and Bmtan, leading to the accumulation of tyrosine and dopa, thereby causing aberrant melanin metabolism and loss of epidermal markings. By contrast, BmERR overexpression enhanced the pathway, resulting in intensification of epidermal markings. The homologous gene of the ERR coactivator, BmPPRC1, showed highly consistent expression with BmERR in the epidermis. The immunofluorescence signal of BmPPRC1 was localized to the nucleus and highly overlapped with that of BmERR. BmPPRC1 interacts with the AF-2 domain of BmERR, and deletion of this region weakens the regulation of melanin metabolism-related genes in silkworm embryonic cells. The ERR function and mode of action are evolutionarily conserved, and its AF-2 structural domain binds equally well to the coactivator BmPPRC1, providing new perspectives for studying the modulability of insect mottle formation. Author summary: It is known that estrogen-related receptors (ERRs) in vertebrates lack natural ligands and rely on their activation function-2 (AF-2) domain to recruit coactivators for transcriptional regulation. However, insects differ significantly from vertebrates in terms of metabolic regulation, and it remains unclear whether insect ERRs function via coactivators. Therefore, we knocked out the AF-2 domain of ERR in the silkworm and investigated the molecular mechanisms by which ERR regulates insect metabolism. Our results indicate that inhibiting genes related to melanin metabolism leads to the accumulation of tyrosine and DOPA, disrupts melanin production, and results in the loss of epidermal markings. In contrast, overexpression of BmERR enhances this pathway, deepening epidermal markings. We also found that the coactivator homolog BmPPRC1 is co-expressed with BmERR in the epidermis and colocalizes with BmERR in the nucleus. Our finding not only provides fresh insights into the mechanisms of epidermal markings but also broadens the research scope for understanding the biological functions and regulatory networks of ERR and other orphan nuclear receptors in insects.
Related
- 1170 Spatial transcriptomics identifies immune heterogeneity in estrogen receptor positive postpartum breast cancer
- Integrated Transcriptomic and Biochemical Analyses Reveal Coordinated Suppression of ER-Associated Survival Signaling and Activation of ROS-Mediated Stress Responses by Oxidized Graphene Quantum Dots in Estrogen Receptor-Positive Breast Cancer
- Alpha-Lipoic Acid and Saxagliptin Attenuate Ferroptosis-Related Ovarian Injury and Modulate FGF21/NOX4–NRF2/HO-1 Signaling in Letrozole-Induced Polycystic Ovary Syndrome
- Medicinal plant-derived bioactive compounds modulate gut microbiota–host signaling in cancer-related fatigue: a phenotype-to-target framework
- Age-Related Lens Membrane Composition and N101D Deamidation Modulate αA-Crystallin Membrane Interactions Relevant to Cataract.
BibTeX
@article{wu2026domain,
title = {{The AF-2 domain of estrogen-related receptor interacts with PPRC1 to modulate larval epidermal marking in Bombyx mori}},
author = {Jinxin Wu and Die Liu and Haoran Xu and Lingqing Zeng and Ping Lin and Ping Zhao and Guanwang Shen},
journal = {PLOS Genetics},
year = {2026},
month = oct,
doi = {10.1371/journal.pgen.1012339},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012339},
note = {CC BY},
}
RIS
TY - JOUR
TI - The AF-2 domain of estrogen-related receptor interacts with PPRC1 to modulate larval epidermal marking in Bombyx mori
AU - Jinxin Wu
AU - Die Liu
AU - Haoran Xu
AU - Lingqing Zeng
AU - Ping Lin
AU - Ping Zhao
AU - Guanwang Shen
PY - 2026
DA - 2026/10/01
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012339
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012339
AB - Estrogen-related receptors (ERRs) have no natural ligands, vertebrate ERRs rely on their activation function-2 (AF-2) structural domain to recruit coactivators for transcriptional regulation. While metabolic regulation in insects differs significantly from that in vertebrates, it remains unclear whether the regulatory function of insect ERR requires coactivators. Using silkworms as the research subject, this study aims to analyze the molecular mechanisms of ERR-regulated metabolism in insects and refine the metabolic regulatory network. This study applied CRISPR/Cas9 gene editing technology to knock out the AF-2 domain of BmERR in the lepidopteran silkworms and examined its effects on functional role, associated interacting factors, and related physiological processes. Disruption of the BmERR AF-2 domain inhibited the expression of melanin metabolism-related genes BmTH, BmDDC, BmAA-NAT, Bmebony, and Bmtan, leading to the accumulation of tyrosine and dopa, thereby causing aberrant melanin metabolism and loss of epidermal markings. By contrast, BmERR overexpression enhanced the pathway, resulting in intensification of epidermal markings. The homologous gene of the ERR coactivator, BmPPRC1, showed highly consistent expression with BmERR in the epidermis. The immunofluorescence signal of BmPPRC1 was localized to the nucleus and highly overlapped with that of BmERR. BmPPRC1 interacts with the AF-2 domain of BmERR, and deletion of this region weakens the regulation of melanin metabolism-related genes in silkworm embryonic cells. The ERR function and mode of action are evolutionarily conserved, and its AF-2 structural domain binds equally well to the coactivator BmPPRC1, providing new perspectives for studying the modulability of insect mottle formation. Author summary: It is known that estrogen-related receptors (ERRs) in vertebrates lack natural ligands and rely on their activation function-2 (AF-2) domain to recruit coactivators for transcriptional regulation. However, insects differ significantly from vertebrates in terms of metabolic regulation, and it remains unclear whether insect ERRs function via coactivators. Therefore, we knocked out the AF-2 domain of ERR in the silkworm and investigated the molecular mechanisms by which ERR regulates insect metabolism. Our results indicate that inhibiting genes related to melanin metabolism leads to the accumulation of tyrosine and DOPA, disrupts melanin production, and results in the loss of epidermal markings. In contrast, overexpression of BmERR enhances this pathway, deepening epidermal markings. We also found that the coactivator homolog BmPPRC1 is co-expressed with BmERR in the epidermis and colocalizes with BmERR in the nucleus. Our finding not only provides fresh insights into the mechanisms of epidermal markings but also broadens the research scope for understanding the biological functions and regulatory networks of ERR and other orphan nuclear receptors in insects.
SN - 1553-7404
SN - 1553-7390
ER -