Publication Highlights: May 2017-September 2017 CFATG
Publication Highlights: May 2017-September 2017
HOME » Highlights » Publication Highlights: May 2017-September 2017

Publication Highlights: Articles on autophagy research published by french laboratories and selected by CFATG.

The endoplasmic reticulum (ER) forms dynamic contacts with several organelles and membranes, including the plasma membrane, and these contacts are thought to have roles in lipid transport and cell signalling. Recent findings have revealed that they are involved also in organelle biogenesis, since autophagosome formation has been reported at endoplasmic reticulum (ER)-mitochondria contact sites. Here we report that autophagosome biogenesis can occur at ER-plasma membrane contacts as well, suggesting a role in autophagy regulation, by direct implication of the tethering Extended Synaptotagmins (E-Syts) proteins. Autophagy, in turn, can regulate these contacts: we show that E-Syt2 and E-Syt3 expression is affected by cell nutrients status and shear stress, both inducing an autophagy-mediated response. Imaging data revealed that early autophagic markers are recruited to E-Syts-containing domains during autophagy and that inhibition of E-Syts expression leads to a reduction in autophagosome biogenesis. E-Syts are essential for autophagy-associated PI3P synthesis at the cortical ER membrane via the recruitment of VMP1, the stabilizing ER partner of PI3KC3 complex. These results highlight the contribution of ER-plasma membrane tethers in autophagosome biogenesis regulation and herald the importance of membrane contact sites in autophagy.

The EMBO Journal (2017) 36, 2018-2033

Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A-type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells’ nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped Promyelocytic-Nuclear Bodies, identified as novel biomarkers in Progeria. We found that the proteasome inhibitor MG132 induces progerin degradation through macroautophagy and strongly reduces progerin production through downregulation of SRSF-1 and upregulation of SRSF-5, controlling prelamin A mRNA aberrant splicing. MG132 treatment improves cellular HGPS phenotypes, reduces cellular senescence and enhances viability and proliferation in HGPS fibroblasts. MG132 injection in skeletal muscle of LmnaG609G/G609G progeria mice model locally reduces SRSF-1 expression and progerin levels. Altogether, we demonstrate progerin reduction based on MG132 dual action and shed light on a promising class of molecules towards a potential therapy for children with HGPS.

EMBO Molecular Medicine (2017) 9, 1294-1313

Other publications

Comments are closed.