Dangerous Entrapment for NRF2

Progerin, a mutated lamin A, causes the severe premature-aging syndrome Hutchinson-Gilford progeria (HGPS). Kubben et al. present a driving mechanism for HGPS involving trapping of NRF2 at the nuclear periphery by progerin. This local restriction results in impaired NRF2 signaling and chronic oxidative stress. Progerin, a mutated lamin A, causes the severe premature-aging syndrome Hutchinson-Gilford progeria (HGPS). Kubben et al. present a driving mechanism for HGPS involving trapping of NRF2 at the nuclear periphery by progerin. This local restriction results in impaired NRF2 signaling and chronic oxidative stress. Mutations in the lamin A gene cause multiple genetic disorders, most striking being an accelerated-aging syndrome called Hutchinson-Gilford progeria syndrome (HGPS). In HGPS, a mutation results in expression of a truncated lamin A protein, known as progerin, that accumulates at the nuclear membrane and acts in a dominant-negative fashion. HGPS patients suffer from atherosclerosis, display multiple symptoms of premature aging, and have a severely shortened lifespan (Gordon et al., 2014Gordon L.B. Rothman F.G. López-Otín C. Misteli T. Cell. 2014; 156: 400-407Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar). At the cellular level, HGPS cells display aberrant nuclear architecture, genomic instability, and altered redox homeostasis. Progerin may also be relevant to normal aging, as it accumulates in wild-type senescent cells. The pleiotropic effects of progerin have complicated the identification of therapeutic targets for HGPS. In this issue of Cell, Kubben et al., 2016Kubben N. Zhang W. Wang L. Voss T.C. Yang J. Qu J. Liu G. Misteli T. Cell. 2016; 165 (this issue): 1361-1374Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar identify a critical redox sensor, NRF2, as the main downstream effector of progerin, connecting the premature aging phenotype of HGPS to a defect in oxidative stress response. Kubben et al., 2016Kubben N. Zhang W. Wang L. Voss T.C. Yang J. Qu J. Liu G. Misteli T. Cell. 2016; 165 (this issue): 1361-1374Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar performed an RNAi screen to identify factors that alleviate the phenotype of human cells engineered to express progerin and found that upregulation of the NRF2 pathway rescued many of the cellular phenotypes of progeria. NRF2 defends organisms against detrimental effects of reactive oxygen species (ROS) through activation of an array of anti-oxidative and detoxification response genes. HGPS cells are known to display elevated ROS levels, but the underlying cause has not been clear. Looking at NRF2 protein distribution in HGPS cells, the new study found that NRF2 is localized to nuclear periphery where it interacts with both lamin A and progerin, although the interaction is stronger between progerin and NRF2. This result suggests that progerin traps NRF2 at the nuclear membrane, leading to impairment of the NRF2 pathway and increased ROS in HGPS cells. NRF2 knockdown recapitulated many of the progerin phenotypes, while importantly, antioxidants and NRF2-activating compounds, such as Oltipraz, rescued the phenotypes of progerin-expressing cells. Identifying a functional link between progerin and NRF2 may revolutionize the treatment for HGPS by offering the therapeutic option of targeting the NRF2 pathway. Activating NRF2 can ameliorate atherosclerosis, the main cause of death in HGPS patients, by reducing ROS levels and inflammation, may also improve genome stability and prevent the loss of mesenchymal stem cells (MSCs) by improving redox homeostasis. Most importantly, Oltipraz is an FDA-approved drug, and additional compounds with similar modes of action should be accessible through chemical screens. The involvement of the NRF2 pathway in the etiology of HGPS provides a novel view on the role of lamins in the aging process. At the cellular level, aging is characterized by genome instability, transcriptional and epigenetic changes, macromolecular damage, inflammation, stem cell exhaustion, and cellular senescence. Nuclear lamins not only provide a scaffold for the nucleus, but also regulate such processes as DNA maintenance, chromatin organization, and transcription, all of which are disrupted in HGFS and also affected in normal aging. In addition to the interaction between lamin A and NRF2 (Kubben et al., 2016Kubben N. Zhang W. Wang L. Voss T.C. Yang J. Qu J. Liu G. Misteli T. Cell. 2016; 165 (this issue): 1361-1374Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar), a recent report showed that lamin A also interacts with SIRT6 (Ghosh et al., 2015Ghosh S. Liu B. Wang Y. Hao Q. Zhou Z. Cell Rep. 2015; 13: 1396-1406Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar), another gene implicated in longevity. SIRT6, a predominantly nuclear protein, catalyzes both deacetylation and mono-ADP ribosylation reactions and is involved in heterochromatin maintenance, transcriptional regulation, DNA repair, and repression of transposable elements (Kugel and Mostoslavsky, 2014Kugel S. Mostoslavsky R. Trends Biochem. Sci. 2014; 39: 72-81Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, Van Meter et al., 2014Van Meter M. Kashyap M. Rezazadeh S. Geneva A.J. Morello T.D. Seluanov A. Gorbunova V. Nat. Commun. 2014; 5: 5011Crossref PubMed Scopus (239) Google Scholar). Lamin A stimulates both biochemical activities of SIRT6, which may be critical for the regulation of SIRT6 in the context of chromatin and higher-order nuclear structure. While progerin impairs NRF2 function by sequestering it at the nuclear membrane, it similarly impairs SIRT6 function by failing to activate SIRT6. Progerin competes with lamin A and impedes SIRT6 localization to damaged DNA upon genotoxic stress (Ghosh et al., 2015Ghosh S. Liu B. Wang Y. Hao Q. Zhou Z. Cell Rep. 2015; 13: 1396-1406Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). Intriguingly, NRF2 appears to require SIRT6 to activate its transcriptional targets (Pan et al., 2016Pan H. Guan D. Liu X. Li J. Wang L. Wu J. Zhou J. Zhang W. Ren R. Zhang W. et al.Cell Res. 2016; 26: 190-205Crossref PubMed Scopus (213) Google Scholar) as the NRF2 pathway is impaired in Sirt6 knockout cells and SIRT6 directly recruits RNA polymerase II to the NRF2 target gene promoter. There are similarities between NRF2, lamin A, and SIRT6 functions. While NRF2 is the central redox sensor in the cells, SIRT6 has also been implicated in stimulating DNA repair in response to oxidative stress (Mao et al., 2011Mao Z. Hine C. Tian X. Van Meter M. Au M. Vaidya A. Seluanov A. Gorbunova V. Science. 2011; 332: 1443-1446Crossref PubMed Scopus (591) Google Scholar). Furthermore, NRF2, lamin A, and SIRT6 have all been implicated in MSC maintenance (Pan et al., 2016Pan H. Guan D. Liu X. Li J. Wang L. Wu J. Zhou J. Zhang W. Ren R. Zhang W. et al.Cell Res. 2016; 26: 190-205Crossref PubMed Scopus (213) Google Scholar, Zhang et al., 2011Zhang J. Lian Q. Zhu G. Zhou F. Sui L. Tan C. Mutalif R.A. Navasankari R. Zhang Y. Tse H.F. et al.Cell Stem Cell. 2011; 8: 31-45Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar). MSCs bearing the HGPS mutation display sensitivity to stress and low viability. Similarly, MSCs deficient for SIRT6 are sensitive to oxidative stress due to the lack of NRF2 activation and show premature cell attrition. These similarities further suggest that lamin A, NRF2, and SIRT6 work together to provide longevity assurance. Taken together, these observations suggest a model (Figure 1) in which lamin A binds and controls factors involved in regulation of transcription and chromatin architecture. Lamin A binds NRF2 and SIRT6, directing transcription of antioxidant genes and promoting genome stability. It is possible that lamin A facilitates the formation of functional complexes between NRF2 and SIRT6 as SIRT6 is required to transcriptionally activate NRF2 targets. Thus, the presence of functional lamin A is important to ensure proper spatial and temporal activation of NRF2 targets. In the presence of progerin, NRF2 is sequestered at the nuclear periphery, reducing its availability. In addition, progerin may impair the formation of functional complexes between NRF2 and SIRT6, further reducing the function of the NRF2 pathway. Increased ROS and inactive SIRT6 protein can lead to accumulation of DNA damage, inefficient DNA repair, and loss of heterochromatin, proposed to be the driving force of aging (Gorbunova and Seluanov, 2016Gorbunova V. Seluanov A. Mutat. Res. 2016; (Published online February 15, 2016)https://doi.org/10.1016/j.mrfmmm.2016.02.004Crossref PubMed Scopus (55) Google Scholar, Tsurumi and Li, 2012Tsurumi A. Li W.X. Epigenetics. 2012; 7: 680-688Crossref PubMed Scopus (122) Google Scholar). In the future, it would be critical to identify specific epigenetic factors such as chromatin remodelers that mediate the effects of NRF2 and SIRT6 on transcription and chromatin architecture and identify how these factors become impaired during aging. The new results from Kubben et al., 2016Kubben N. Zhang W. Wang L. Voss T.C. Yang J. Qu J. Liu G. Misteli T. Cell. 2016; 165 (this issue): 1361-1374Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar identify impaired NRF2 signaling as the key factor in HGPS progression. Together with other recent results, this finding defines a lamin A/NRF2/SIRT6 network at the core of aging-related pathways. These results put us closer to understanding the mechanisms of normal aging and developing therapeutic strategies to slow down the aging process. Repression of the Antioxidant NRF2 Pathway in Premature AgingKubben et al.CellJune 02, 2016In BriefImpairment of the NRF2 pathway is a key contributor to premature aging in Hutchinson-Gilford progeria syndrome (HGPS) via increasing chronic oxidative stress that recapitulates HGPS aging defects. Full-Text PDF Open Archive