Dyskerin Downregulation Can Induce ER Stress and Promote Autophagy via AKT-mTOR Signaling Deregulation

: Dyskerin is an evolutionarily conserved nucleolar protein implicated in a wide range of fundamental biological roles, including telomere maintenance and ribosome biogenesis. Germline mutations of DKC1, the human gene encoding dyskerin, cause the hereditary disorders known as X-linked dyskeratosis congenita (X-DC). Moreover, dyskerin is upregulated in several cancers. Due to the pleiotropic functions of dyskerin, the X-DC clinical features overlap with those of both telomeropathies and ribosomopathies. In this paper, we evaluate the telomerase-independent effects of dyskerin depletion on cellular physiology by using inducible DCK1 knockdown. This system allows the downregulation of DKC1 expression within a short timeframe. We report that, in these cellular systems, dyskerin depletion induces the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum, which in turn induces the activation of the PERK branch of the unfolded protein response. We also demonstrate that the PERK-eIF2a-ATF4-CHOP signaling pathway, activated by dyskerin downregulation, triggers a functional autophagic flux through the inhibition of the PI3K/AKT/mTOR pathway. By revealing a novel unpredicted connection between the loss of dyskerin, autophagy and UPR, our results establish a firm link between the lowering of dyskerin levels and the activation of the ER stress response, that plays a key role in the pathogenesis of several diseases

Genetic approaches to find innovative biotechnological strategies for an eco-sustainable fight against Aedes albopictus mosquito.

The research of this doctoral project focuses on the study of the Asian tiger mosquito Aedes albopictus. This mosquito is an aggressive and epidemiologically imposing insect since its geographical area has considerably expanded in recent decades. It is one of the 100 most invasive species in the world and its territory is rapidly spreading due to its tolerance to egg drying, different environmental adaptations, photoperiodic diapause and resistance to insecticides (Li et al., 2014; Li et al., 2018; Xia et al. al., 2018). The A. albopictus sex determination pathway has been investigated for its regulatory mechanisms. In addition, new gene targets have been identified in order to design novel sex separation systems that can contribute to the development of eco-sustainable strategies for the control and eradication of this invasive and dangerous mosquito species. Finally, through field activities, it was possible to monitor the distribution of A. albopictus on the Island of Procida (NA) by actively involving citizens, according to the "Citizen-science" model