In Hutchinson-Gilford progeria syndrome (HGPS), dysfunctional autophagy results in the accumulation of progerin, a lamin A mutant variant that alters a plethora of processes, inducing senescence and driving premature aging. Therefore, the elimination of progerin through autophagy restoration emerges as a therapeutic intervention against HGPS. However, a comprehensive study of autophagy flux in HGPS remains to be addressed. In this study, the dynamics of autophagy in HGPS fibroblasts were analyzed utilizing different HGPS cell models and experimental approaches. The autophagy-associated transcriptomic profile was determined, and the autophagy-lysosome axis was comprehensively analyzed. We demonstrated that progerin induces the formation of autophagosomes but impairs their maturation and subsequent fusion with lysosomes. This alteration is attributed in part to the progerin-mediated decreased expression of STX17, a marker of mature autophagosomes, and LAMP1, a membrane lysosomal protein, as well as the presence of defective lysosomes. In line with this, the rescue of STX17 and LAMP1 expression improved autophagy flux. Interestingly, treatment of HGPS fibroblasts with Selinexor, an autophagy activator, elicited nuclear accumulation of TFEB and enhanced lysosomal biogenesis and function, thereby activating autophagy. Selinexor treatment improved both autophagosome maturation and autophagosome-lysosome fusion, which ultimately led to effective autophagic degradation of progerin. In summary, progerin impedes proper autophagy flux, thus preventing its own autophagic degradation, which underscores the relevance of targeting the autophagy-lysosome pathway to counteract the toxic accumulation of progerin.

Removal of circulating plasma low-density lipoprotein cholesterol (LDL-C) by the liver relies on efficient endocytosis and intracellular vesicle trafficking. Increasing the availability of hepatic LDL receptors (LDLRs) remains a major clinical target for reducing LDL-C levels. Here, we describe a novel role for RNF130 (ring finger containing protein 130) in regulating plasma membrane availability of LDLR.

Myeloid cells are known mediators of hypertension, but their role in initiating renin-induced hypertension has not been studied. Vitamin D deficiency causes pro-inflammatory macrophage infiltration in metabolic tissues and is linked to renin-mediated hypertension. We tested the hypothesis that impaired vitamin D signaling in macrophages causes hypertension using conditional knockout of the myeloid vitamin D receptor in mice (KODMAC). These mice develop renin-dependent hypertension due to macrophage infiltration of the vasculature and direct activation of renal juxtaglomerular (JG) cell renin production. Induction of endoplasmic reticulum stress in knockout macrophages increases miR-106b-5p secretion, which stimulates JG cell renin production via repression of transcription factors E2f1 and Pde3b. Moreover, in wild-type recipient mice of KODMAC/miR106b bone marrow, knockout of miR-106b-5p prevents the hypertension and JG cell renin production induced by KODMAC macrophages, suggesting myeloid-specific, miR-106b-5p-dependent effects. These findings confirm macrophage miR-106b-5p secretion from impaired vitamin D receptor signaling causes inflammation-induced hypertension.

The loss of estrogen (E ) initiates a rapid phase of bone loss leading to osteoporosis in one-half of postmenopausal women, but the mechanism is not fully understood. Here, we show for the first time how loss of E activates low-grade inflammation to promote the acute phase of bone catabolic activity in ovariectomized (OVX) mice. E regulates the abundance of dendritic cells (DCs) that express IL-7 and IL-15 by inducing the Fas ligand (FasL) and apoptosis of the DC. In the absence of E , DCs become long-lived, leading to increased IL-7 and IL-15. We find that IL-7 and IL-15 together, but not alone, induced antigen-independent production of IL-17A and TNFα in a subset of memory T cells (T ). OVX of mice with T-cell-specific ablation of IL15RA showed no IL-17A and TNFα expression, and no increase in bone resorption or bone loss, confirming the role of IL-15 in activating the T and the need for inflammation. Our results provide a new mechanism by which E regulates the immune system, and how menopause leads to osteoporosis. The low-grade inflammation is likely to cause or contribute to other comorbidities observed postmenopause. © 2020 American Society for Bone and Mineral Research.

Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease caused by the mutant lamin-A protein “progerin,” features robust sterile inflammation/interferon (IFN)-like response. Targeting inflammation delays cellular and organismal HGPS phenotypes. However, specific mechanisms driving the sterile inflammation/IFN-like response and how this response causes tissue degeneration/loss in HGPS are unknown. We demonstrate that signal transducer and activator of transcription 1 (STAT1) drives the IFN-like response and aging phenotypes in HGPS cellular and mouse models. Calcitriol and baricitinib strongly repress sterile inflammation/IFN-like response, improving hallmarks of progerin-expressing cells such as mitochondrial, autophagy, and proliferation defects. calcitriol or baricitinib extend lifespan of progeria mice, and baricitinib alone or combined with a high-caloric/high-fat diet has a remarkable impact reducing skin, aortic, and adipose tissue degeneration. Critically, Stat1 haploinsufficiency reduces tissue degeneration/loss and extends lifespan of progeria mice, recapitulating baricitinib benefits. Our study unveils STAT1 as a driver of the IFN-like response and HGPS pathology and suggests that aberrant STAT1 signaling contributes to aging, providing new therapeutic possibilities for HGPS and other inflammation/IFN response-associated diseases.