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Sirtuins are key players for maintaining cellular homeostasis and are often deregulated in different human diseases. SIRT7 is the only member of mammalian sirtuins that principally resides in the nucleolus, a nuclear compartment involved in ribosomal biogenesis, senescence, and cellular stress responses. The ablation of SIRT7 induces global genomic instability, premature ageing, metabolic dysfunctions, and reduced stress tolerance, highlighting its critical role in counteracting ageing-associated processes. In this review, we describe the molecular mechanisms employed by SIRT7 to ensure cellular and organismal integrity with particular emphasis on SIRT7-dependent regulation of nucleolar functions.

Idiopathic pulmonary fibrosis (IPF) represents the most aggressive form of pulmonary fibrosis (PF) and is a highly debilitating disorder with a poorly understood etiology. The lung epithelium seems to play a critical role in the initiation and progression of the disease. A repeated injury of lung epithelial cells prompts type II alveolar cells to secrete pro-fibrotic cytokines, which induces differentiation of resident mesenchymal stem cells into myofibroblasts, thus promoting aberrant deposition of extracellular matrix (ECM) and formation of fibrotic lesions. Reactivation of developmental pathways such as the Wnt-β-catenin signaling cascade in lung epithelial cells plays a critical role in this process, but the underlying mechanisms are still enigmatic. Here, we demonstrate that the membrane-associated protein NUMB is required for pathological activation of β-catenin signaling in lung epithelial cells following bleomycin-induced injury. Importantly, depletion of Numb and Numblike reduces accumulation of fibrotic lesions, preserves lung functions, and increases survival rates after bleomycin treatment of mice. Mechanistically, we demonstrate that NUMB interacts with casein kinase 2 (CK2) and relies on CK2 to activate β-catenin signaling. We propose that pharmacological inhibition of NUMB signaling may represent an effective strategy for the development of novel therapeutic approaches against PF.

Giant cell arteritis (GCA), medium and large vessel granulomatous vasculitis affecting the elderly, is characterized by a multitude of vascular complications, including venous thrombosis, myocardial infraction and stroke. The formation of granulomatous infiltrates and the enhanced accumulation of proinflammatory cytokines are typical features of this condition. The GCA pathogenesis remains largely unknown, but recent studies have suggested the involvement of oxidative stress, mainly sustained by an enhanced reactive oxygen species (ROS) production by immature neutrophils. On this basis, in the present study, we intended to evaluate, in GCA patients, the presence of systemic oxidative stress and possible alterations in the expression level of nuclear sirtuins, enzymes involved in the inhibition of inflammation and oxidative stress. Thirty GCA patients were included in the study and compared to 30 healthy controls in terms of leukocyte ROS production, oxidative stress and SIRT1 expression. Our results clearly indicated a significant increase (p < 0.05) both in the ROS levels in the leukocyte fractions and plasma oxidative stress markers (lipid peroxidation and total antioxidant capacity) in the GCA patients compared to the healthy controls. In PBMCs from the GCA patients, a significant decrease in SIRT1 expression (p < 0.05) but not in SIRT6 and SIRT7 expression was found. Taken together, our preliminary findings indicate that, in GCA patients, plasma oxidative stress is paralleled by a reduced SIRT1 expression in PBMC. Further studies are needed to highlight if and how these alterations contribute to GCA pathogenesis.

Adaptation to different forms of environmental stress is crucial for maintaining essential cellular functions and survival. The nucleolus plays a decisive role as a signaling hub for coordinating cellular responses to various extrinsic and intrinsic cues. p53 levels are normally kept low in unstressed cells, mainly due to E3 ubiquitin ligase MDM2-mediated degradation. Under stress, nucleophosmin (NPM) relocates from the nucleolus to the nucleoplasm and binds MDM2, thereby preventing degradation of p53 and allowing cell-cycle arrest and DNA repair. Here, we demonstrate that the mammalian sirtuin SIRT7 is an essential component for the regulation of p53 stability during stress responses induced by ultraviolet (UV) irradiation. The catalytic activity of SIRT7 is substantially increased upon UV irradiation through ataxia telangiectasia mutated and Rad3 related (ATR)-mediated phosphorylation, which promotes efficient deacetylation of the SIRT7 target NPM. Deacetylation is required for stress-dependent relocation of NPM into the nucleoplasm and MDM2 binding, thereby preventing ubiquitination and degradation of p53. In the absence of SIRT7, stress-dependent stabilization of p53 is abrogated, both in vitro and in vivo, impairing cellular stress responses. The study uncovers an essential SIRT7-dependent mechanism for stabilization of the tumor suppressor p53 in response to genotoxic stress.

Release of nucleophosmin (NPM) from nucleoli following stress promotes rapid stabilization of the tumor suppressor p53 (TP53, best known as p53). Nucleoplasmic NPM binds to the ubiquitin ligase mouse double minute 2 (MDM2) and prevents MDM2-dependent p53 degradation. We recently demonstrated that sirtuin 7 (SIRT7) activates this pathway by directly deacetylating NPM following ultraviolet irradiation, indicating tumor-suppressive functions of SIRT7.