TY - JOUR
T1 - Cadmium hijacks the high zinc response by binding and activating the HIZR-1 nuclear receptor
AU - Earley, Brian J.
AU - Cubillas, Ciro
AU - Warnhoff, Kurt
AU - Ahmad, Raheel
AU - Alcantar, Alan
AU - Lyon, Maximilian D.
AU - Schneider, Daniel L.
AU - Kornfeld, Kerry
N1 - Funding Information:
ACKNOWLEDGMENTS. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (grant P40 OD010440) and the National BioResource Project for the Experimental Animal “Nematode C. elegans.” Funding from NIH (grant R01 GM068598 received by K.K. and grant F31 ES030622 received by B.J.E.) supported this study.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/10/19
Y1 - 2021/10/19
N2 - Cadmium is an environmental pollutant and significant health hazard that is similar to the physiological metal zinc. In Caenorhabditis elegans, high zinc homeostasis is regulated by the high zinc activated nuclear receptor (HIZR-1) transcription factor. To define relationships between the responses to high zinc and cadmium, we analyzed transcription. Many genes were activated by both high zinc and cadmium, and hizr-1 was necessary for activation of a subset of these genes; in addition, many genes activated by cadmium did not require hizr-1, indicating there are at least two mechanisms of cadmium-regulated transcription. Cadmium directly bound HIZR-1, promoted nuclear accumulation of HIZR-1 in intestinal cells, and activated HIZR-1-mediated transcription via the high zinc activation (HZA) enhancer. Thus, cadmium binding promotes HIZR-1 activity, indicating that cadmium acts as a zinc mimetic to hijack the high zinc response. To elucidate the relationships between high zinc and cadmium detoxification, we analyzed genes that function in three pathways: the pcs-1/phytochelatin pathway strongly promoted cadmium resistance but not high zinc resistance, the hizr-1/HZA pathway strongly promoted high zinc resistance but not cadmium resistance, and the mek-1/sek-1/kinase signaling pathway promoted resistance to high zinc and cadmium. These studies identify resistance pathways that are specific for high zinc and cadmium, as well as a shared pathway.
AB - Cadmium is an environmental pollutant and significant health hazard that is similar to the physiological metal zinc. In Caenorhabditis elegans, high zinc homeostasis is regulated by the high zinc activated nuclear receptor (HIZR-1) transcription factor. To define relationships between the responses to high zinc and cadmium, we analyzed transcription. Many genes were activated by both high zinc and cadmium, and hizr-1 was necessary for activation of a subset of these genes; in addition, many genes activated by cadmium did not require hizr-1, indicating there are at least two mechanisms of cadmium-regulated transcription. Cadmium directly bound HIZR-1, promoted nuclear accumulation of HIZR-1 in intestinal cells, and activated HIZR-1-mediated transcription via the high zinc activation (HZA) enhancer. Thus, cadmium binding promotes HIZR-1 activity, indicating that cadmium acts as a zinc mimetic to hijack the high zinc response. To elucidate the relationships between high zinc and cadmium detoxification, we analyzed genes that function in three pathways: the pcs-1/phytochelatin pathway strongly promoted cadmium resistance but not high zinc resistance, the hizr-1/HZA pathway strongly promoted high zinc resistance but not cadmium resistance, and the mek-1/sek-1/kinase signaling pathway promoted resistance to high zinc and cadmium. These studies identify resistance pathways that are specific for high zinc and cadmium, as well as a shared pathway.
KW - Cadmium transcriptional response
KW - Nuclear receptor
KW - Zinc homeostasis
KW - Zinc sensor
UR - http://www.scopus.com/inward/record.url?scp=85117280023&partnerID=8YFLogxK
U2 - 10.1073/pnas.2022649118
DO - 10.1073/pnas.2022649118
M3 - Article
C2 - 34649987
AN - SCOPUS:85117280023
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 42
M1 - e2022649118
ER -