Biology subjects

De Matteis, M. A.

Publications and source records attributed to De Matteis, M. A..

3 recordsLinked to original sources

bioRxiv2023

Role of trafficking protein particle complex 2 in medaka development

The skeletal dysplasia spondyloepiphyseal dysplasia tarda (SEDT) is caused by mutations in the TRAPPC2 gene, which encodes Sedlin, a component of the trafficking protein particle (TRAPP) complex that we have shown previously to be required for the export of type II collagen (Col2) from the endoplasmic reticulum. No vertebrate model for SEDT has been generated thus far. To address this gap, we generated a Sedlin knockout animal by mutating the orthologous TRAPPC2 gene (olSedl) of Oryzias latipes (medaka) fish. OlSedl deficiency leads to embryonic defects, short size, diminished skeletal ossification, and altered Col2 production and secretion, resembling human defects observed in SEDT patients. Moreover, SEDT knock-out animals display photoreceptor degeneration and gut morphogenesis defects, suggesting a key role for Sedlin in the development of these organs. Thus, by studying Sedlin function in vivo, we provide evidence for a mechanistic link between TRAPPC2-mediated membrane trafficking, Col2 export, and developmental disorders.

cell biology↗

bioRxiv2021

Defective endosome-TGN retrograde transport promotes NLRP3 inflammasome activation

Inflammasome complexes are pivotal in the innate immune response to pathogens and other danger signals1-4. The NLRP3 inflammasome is activated in response to a broad variety of cellular stressors. Most of the stimuli act in a potassium efflux-dependent manner but a primary and converging sensing mechanism by the NLRP3 receptor initiating inflammasome assembly remains ill-defined. Here we show that NLRP3 activators disrupt endosome-TGN retrograde transport (ETRT) and lead to localization of NLRP3 to endosomal vesicles. Genetic and pharmacologic perturbation of ETRT leads to accumulation of phosphoinositol-4-phosphate (PI4P) in endosomes to which NLRP3 is recruited. Disruption of ETRT potentiates NLRP3 inflammasome activation in murine and human macrophages in vitro. Mice with defects in ETRT in the myeloid compartment are more susceptible to LPS-induced sepsis showing enhanced mortality and IL-1{beta} serum levels as compared to control animals. Our study thus uncovers that changes in endocytic trafficking mediate NLRP3-dependent inflammatory responses.

immunology↗

bioRxiv2019

The TRAPP complex mediates secretion arrest induced by stress granule assembly

The TRAnsport-Protein-Particle (TRAPP) complex controls multiple membrane trafficking steps and is thus strategically positioned to mediate cell adaptation to diverse environmental conditions, including acute stress. We have identified TRAPP as a key component of a branch of the integrated stress response that impinges on the early secretory pathway. TRAPP associates with and drives the recruitment of the COPII coat to stress granules (SGs) leading to vesiculation of the Golgi complex and an arrest of ER export. Interestingly, the relocation of TRAPP and COPII to SGs only occurs in actively proliferating cells and is CDK1/2-dependent. We show that CDK1/2 activity controls the COPII cycle at ER exit sites (ERES) and that its inhibition prevents TRAPP/COPII relocation to SGs by stabilizing them at the ERES. Importantly, TRAPP is not just a passive constituent of SGs but controls their maturation since SGs that assemble in TRAPP-depleted cells are smaller and are no longer able to recruit RACK1 and Raptor, rendering the cells more prone to undergo apoptosis upon stress exposure.

cell biology↗