Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function

Abstract

Sestrin2 is a stress-inducible metabolic regulator and a conserved antioxidant protein which has been implicated in the pathogenesis of several diseases. Sestrin2 can protect against atherosclerosis, heart failure, hypertension, myocardial infarction, stroke, spinal cord injury neurodegeneration, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, acute kidney injury (AKI), chronic kidney disease (CKD), and pulmonary inflammation. Oxidative stress and cellular damage signals can alter the expression of Sestrin2 to compensate for organ damage. Different stress signals such as those mediated by P53, Nrf2/ARE, HIF-1α, NF-κB, JNK/c-Jun, and TGF-β/Smad signaling pathways can induce Sestrin2 expression. Subsequently, Sestrin2 activates Nrf2 and AMPK. Furthermore, Sestrin2 is a major negative regulator of mTORC1. Sestrin2 indirectly regulates the expression of several genes and reprograms intracellular signaling pathways to attenuate oxidative stress and modulate a large number of cellular events such as protein synthesis, cell energy homeostasis, mitochondrial biogenesis, autophagy, mitophagy, endoplasmic reticulum (ER) stress, apoptosis, fibrogenesis, and lipogenesis. Sestrin2 vigorously enhances M2 macrophage polarization, attenuates inflammation, and prevents cell death. These alterations in molecular and cellular levels improve the clinical presentation of several diseases. This review will shed light on the beneficial effects of Sestrin2 on several diseases with an emphasis on underlying pathophysiological effects.

Figure 1

The molecular mechanisms underlying the protective effects of Sestrin2 on cardiovascular diseases. Sestrin2 releases Nrf2 through autophagic degradation of Keap1. Activated Nrf2 binds to ARE of antioxidant genes and promotes the expression of Sestrin2 and other antioxidants. Sestrin2 can inhibit NADHP oxidase. Attenuation of oxidative stress by Sestrin2 and other antioxidants suppresses the inflammatory response and attenuates ASK1-mediated apoptosis. Sestrin2 also activates the LKB1/AMPK/TSC2 pathway to inhibit mTROC1. Besides, Sestrin2 attenuates the inhibitory effect of GATOR2 on GATOR1, thereby inhibiting mTORC1. mTORC1 activation accelerates protein synthesis leading to deposition of a large amount of misfolded protein during inflammation and stimulating ER stress. Furthermore, mTORC1 activation downregulates autophagy and mitophagy by inhibiting ULK1 and other activators of autophagy. Sestrin2-induced inhibition of mTORC1 enhances autophagy and mitophagy and inhibits ER stress. AMPK activation by Sestrin2 improves mitochondrial biogenesis through upregulation of PGC-1α. AMPK inhibits Ang-II- and ERK-induced cardiovascular remodeling. Sestrin2 also attenuates oxidative stress and activates AMPK to inhibit TLR, NF-κB, JNK, and P38 MAPK and confine the inflammatory response.

Figure 2

The protective effect of Sestrin2 on the formation and stability of atherosclerotic plaque. Sestrin2 attenuates oxidative stress and improves autophagy, thereby decreasing inflammation, downregulating the expression of adhesion molecules, and preventing M1 macrophage polarization and foam cell and plaque formation. Furthermore, Sestrin2 can stabilize the preexisting plaques by preventing VSMC apoptosis and MMP release.

Figure 3

The autoregulatory effect of Sestrin2 on major signaling pathways. Several signaling pathways either protective such as Nrf2/ARE or destructive such as Ang-II, JNK/c-Jun, HIF-1α, NF-κB, and TGF-β/Smad can induce Sestrin2 expression. In return, Sestrin2 selectively augments protective mechanisms and attenuates destructive signaling pathways.

Figure 4

The protective effects of Sestrin2 on liver diseases. Similar to the cardiovascular system, Sestrin2 activates Nrf2 in the liver, thereby increasing the gene expression of itself and other antioxidants and attenuating oxidative stress. Also, Sestrin2 can improve insulin resistance, autophagy, mitophagy, and ER stress by activating the AMPK/mTORC1 axis. Upregulation of PGC-1α by Sestrin2 helps to improve mitochondrial biogenesis and prevent NHE1-mediated intrahepatic fat accumulation. Furthermore, Sestrin2 can prevent de novo lipogenesis by attenuating LXRα- and mTORC1-mediated SREBP-1c upregulation. Activation of Nrf2 and APMK/Sirt1 signaling also contributes to inhibiting LXRα-induced de novo lipogenesis. Sestrin2 is needed for competent function of mitochondrial complexes, and inadequate Sestrin2 expression impairs ATP production. Sestrin2 inhibits the major positive regulators of inflammatory signaling such as TLR, JNK, NLRP3, P38 MAPK, and AP-1 to prevent Kupffer cell activation and decrease cytokine release. Sestrin2 modulates TGF-β/Smad-mediated activation of stellate cells and hinders EMT to suppress liver fibrogenesis. These alterations alleviate liver inflammation, prevent intrahepatic fat deposition, and ameliorate liver fibrosis.

Figure 5

The protective effect of Sestrin2 on several organs. Sestrin2 can alleviate the diseases of several organs. It enhances the function of cardiovascular system, nervous system, respiratory system, liver, and kidney. It alleviates inflammation, prevents airway remodeling in the respiratory system, protects against liver and renal fibrosis, and mitigates NAFLD and AKI. Furthermore, Sestrin2 can profoundly improve cardiovascular and neuronal diseases. It ameliorates neuropathy, spinal cord injury, traumatic brain injury, retinal damage, hair cells damage, stroke, Parkinson's disease, and Alzheimer's disease. Sestrin2 can also enormously protect against myocardial infarction, arrhythmias, heart failure, atherosclerosis, hypertension, and cardiomyopathy.