Research Articles

The primary cilium protein folliculin is part of the autophagy signaling pathway to regulate epithelial cell size in response to fluid flow

Naïma Zemirli^1,2,#, Asma Boukhalfa^1,2,#, Nicolas Dupont^1,2, Joëlle Botti^1,3, Patrice Codogno^1,2 and Etienne Morel^1,2

Autophagy is a conserved molecular pathway directly involved in the degradation and recycling of intracellular components. Autophagy is associated with a response to stress situations, such as nutrients deficit, chemical toxicity, mechanical stress or microbial host defense. We have recently shown that primary cilium-dependent autophagy is important to control kidney epithelial cell size in response to fluid flow induced shear stress. Here we show that the ciliary protein folliculin (FLCN) actively participates to the signaling cascade leading to the stimulation of fluid flow-dependent autophagy upstream of the cell size regulation in HK2 kidney epithelial cells. The knockdown of FLCN induces a shortening of the primary cilium, inhibits the activation of AMPK and the recruitment of the autophagy protein ATG16L1 at the primary cilium. Altogether, our results suggest that FLCN (...)

p38β MAPK mediates ULK1-dependent induction of autophagy in skeletal muscle of tumor-bearing mice

Zhelong Liu^{1, 2,†}, Ka Wai Thomas Sin^1,†, Hui Ding^1,3, HoangAnh Amy Doan¹, Song Gao¹, Hongyu Miao⁴, Yahui Wei^1,#, Yiman Wang^1,#, Guohua Zhang¹, and Yi-Ping Li¹

INTRODUCTION Cancer has been increasingly recognized as a systemic disorder that stresses multiple organs independent of its location. At least 50% of cancer patients experience cachexia, a systemic wasting syndrome

Assay for high-throughput screening of inhibitors of the ASC-PYD inflammasome core filament

Lorenzo Sborgi¹, Johanna Ude¹, Mathias S. Dick¹, Jonathan Vesin², Marc Chambon², Gerardo Turcatti², Petr Broz¹, Sebastian Hiller¹

The protein ASC is a central component of most inflammasome complexes, forming functional oligomeric filaments that activate large amounts of pro-caspase-1 for further IL-1β processing and the induction of Gasdermin D-dependent cell death. The central role of inflammasomes in the innate immune response pose them as new molecular targets for therapy of diverse acute, chronic and inherited autoinflammatory pathologies. In recent years, an increasing number of molecules were proposed to modulate inflammasome signalling by interacting with different components of inflammasome complexes. However, the difficult in vitro reconstitution of the inflammasome has limited the development of specific on-target biochemical assays for compound activity confirmation and for drug discovery in high throughput screening setups. Here we describe a homogeneous, pH (...)

Dram1 regulates DNA damage-induced alternative autophagy

Meruna Nagata¹, Satoko Arakawa¹, Hirofumi Yamaguchi¹, Satoru Torii¹, Hazuki Endo¹, Masatsune Tsujioka¹, Shinya Honda¹, Yuya Nishida¹, Akimitsu Konishi^1,2, Shigeomi Shimizu¹

Autophagy is an evolutionarily conserved process that degrades subcellular constituents. Mammalian cells undergo two types of autophagy; Atg5-dependent conventional autophagy and Atg5-independent alternative autophagy, and the molecules required for the latter type of autophagy are largely unknown. In this study, we analyzed the molecular mechanisms of genotoxic stress-induced alternative autophagy, and identified the essential role of p53 and damage-regulated autophagy modulator (Dram1). Dram1 was sufficient to induce alternative autophagy. In the mechanism of alternative autophagy, Dram1 functions in the closure of isolation membranes downstream of p53. These findings indicate that Dram1 plays a pivotal role in genotoxic stress-induced alternative autophagy.

The role of hydrophobic matching on transmembrane helix packing in cells

Brayan Grau¹, Matti Javanainen^2,3, Maria Jesús García-Murria¹, Waldemar Kulig^2,3, Ilpo Vattulainen^2,3,4, Ismael Mingarro¹, Luis Martínez-Gil¹

INTRODUCTION Assembly of the native structure of most integral membrane proteins takes place in two main steps [cite source=’pubmed’]1694455[/cite]. The first step includes targeting and insertion of the protein into

mIDH-associated DNA hypermethylation in acute myeloid leukemia reflects differentiation blockage rather than inhibition of TET-mediated demethylation

Laura Wiehle¹, Günter Raddatz¹, Stefan Pusch^2,3, Julian Gutekunst¹, Andreas von Deimling^2,3, Manuel Rodríguez-Paredes¹ and Frank Lyko¹

INTRODUCTION Isocitrate dehydrogenase enzymes IDH1 and IDH2 are two closely related enzymes that convert isocitrate to α-ketoglutarate in the tricarboxylic acid (TCA) cycle. The genes encoding IDH1 and IDH2 are

The long non-coding RNA H19 suppresses carcinogenesis and chemoresistance in hepatocellular carcinoma

Christina S. Schultheiss^1,§, Stephan Laggai^1,§, Beate Czepukojc¹, Usama K. Hussein^1,2, Markus List³, Ahmad Barghash⁴, Sascha Tierling⁵, Kevan Hosseini¹, Nicole Golob-Schwarzl⁶, Juliane Pokorny⁷, Nina Hachenthal¹, Marcel Schulz^3,9, Volkhard Helms¹⁰, Jörn Walter⁵, Vincent Zimmer⁸, Frank Lammert⁸, Rainer M. Bohle⁷, Luisa Dandolo¹¹, Johannes Haybaeck^6,12, Alexandra K. Kiemer^1,*, Sonja M. Kessler^1,6

The long non-coding RNA (lncRNA) H19 represents a maternally expressed and epigenetically regulated imprinted gene product and is discussed to have either tumor-promoting or tumor-suppressive actions. Recently, H19 was shown to be regulated under inflammatory conditions. Therefore, aim of this study was to determine the function of H19 in hepatocellular carcinoma (HCC), an inflammation-associated type of tumor. In four different human HCC patient cohorts H19 was distinctly downregulated in tumor tissue compared(...)