Nrf2 drives oxidative stress-induced autophagy in nucleus pulposus cells via a Keap1/Nrf2/p62 feedback loop to protect intervertebral disc from degeneration

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Abstract

Intervertebral disc (IVD) degeneration is known to aggravate with age and oxidative stress is implicated in the pathogenesis of many age-related diseases. Nuclear factor (erythroid-derived-2)-like 2 (Nrf2) can confer adaptive protection against oxidative and proteotoxic stress in cells. In this study, we assessed whether Nrf2 can protect against oxidative stress in nucleus pulposus (NP) cells. In addition, we investigated Nrf2 expression in NP tissue samples from patients with different degrees of IVD degeneration and a mouse model of aging and IVD degeneration and the influence of H2O2-induced oxidative stress on autophagic pathways in NP cells. Autophagy was assessed by measuring levels of autophagy-related protein (ATG) family members and the autophagic markers, p62 and LC3. We found that expression of Nrf2 progressively decreased in human NP tissue samples of patients with increasing degrees of IVD degeneration. Nrf2 deficiency leads to the degeneration of IVDs during aging. Nrf2 knockout also aggravates IVD degeneration and reduces autophagic gene expression in an induced mouse model of IVD degeneration. The detrimental effects of H2O2-induced oxidative stress were increased in autophagy-deficient cells via reduced expression of Atg7 and the Keap1–Nrf2–p62 autophagy pathway. Taken together, these results suggest that excessive oxidative stress causes the upregulation of autophagy, and autophagy acts as an antioxidant feedback response activated by a Keap1-Nrf2-p62 feedback loop in IVD degeneration.

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Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto (2011)

The Keap1–Nrf2 regulatory pathway plays a central role in the protection of cells against oxidative and xenobiotic damage. Under unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3–Keap1 ubiquitin E3 ligase complex and rapidly degraded in proteasomes. Upon exposure to electrophilic and oxidative stresses, reactive cysteine residues of Keap1 become modified, leading to a decline in the E3 ligase activity, stabilization of Nrf2 and robust induction of a battery of cytoprotective genes. Biochemical and structural analyses have revealed that the intact Keap1 homodimer forms a cherry-bob structure in which one molecule of Nrf2 associates with two molecules of Keap1 by using two binding sites within the Neh2 domain of Nrf2. This two-site binding appears critical for Nrf2 ubiquitination. In many human cancers, missense mutations in KEAP1 and NRF2 genes have been identified. These mutations disrupt the Keap1–Nrf2 complex activity involved in ubiquitination and degradation of Nrf2 and result in constitutive activation of Nrf2. Elevated expression of Nrf2 target genes confers advantages in terms of stress resistance and cell proliferation in normal and cancer cells. Discovery and development of selective Nrf2 inhibitors should make a critical contribution to improved cancer therapy.

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Takao Hanada, Nobuo Noda, Yoshinori Satomi … (2007)

Autophagy is a bulk degradation process in eukaryotic cells; autophagosomes enclose cytoplasmic components for degradation in the lysosome/vacuole. Autophagosome formation requires two ubiquitin-like conjugation systems, the Atg12 and Atg8 systems, which are tightly associated with expansion of autophagosomal membrane. Previous studies have suggested that there is a hierarchy between these systems; the Atg12 system is located upstream of the Atg8 system in the context of Atg protein organization. However, the concrete molecular relationship is unclear. Here, we show using an in vitro Atg8 conjugation system that the Atg12-Atg5 conjugate, but not unconjugated Atg12 or Atg5, strongly enhances the formation of the other conjugate, Atg8-PE. The Atg12-Atg5 conjugate promotes the transfer of Atg8 from Atg3 to the substrate, phosphatidylethanolamine (PE), by stimulating the activity of Atg3. We also show that the Atg12-Atg5 conjugate interacts with both Atg3 and PE-containing liposomes. These results indicate that the Atg12-Atg5 conjugate is a ubiquitin-protein ligase (E3)-like enzyme for Atg8-PE conjugation reaction, distinctively promoting protein-lipid conjugation.

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Degeneration of the intervertebral disc

Jill Urban, Sally Roberts (2003)

The intervertebral disc is a cartilaginous structure that resembles articular cartilage in its biochemistry, but morphologically it is clearly different. It shows degenerative and ageing changes earlier than does any other connective tissue in the body. It is believed to be important clinically because there is an association of disc degeneration with back pain. Current treatments are predominantly conservative or, less commonly, surgical; in many cases there is no clear diagnosis and therapy is considered inadequate. New developments, such as genetic and biological approaches, may allow better diagnosis and treatments in the future.