 |
By Christina Towers, PhD.
Macroautophagy is a cellular recycling process that requires the formation of double membrane structures to engulf and degrade damaged cytoplasmic material. The pathway involves over 20 core autophagy proteins (ATG) and is tightly regulated in response to stress and nutrient availability1. The first step is initiated by the biogenesis of a pre-autophagosome called a phagophore and flagstaff studies identified the endoplasmic reticulum (ER) as the canonical source for these membranes2,3. However recently investigators realized that other organelles could make significant membrane contributions to autophagosome formation including endosomes, mitochondria, and even the plasma membrane (PM)4,5. Indeed, last year in 2017, Dr. Molino and colleagues published a high-profile article in The EMBO Journal showing that interactions between the ER membrane and the plasma membrane are necessary for autophagosome formation6.
Nascimbeni et al. used electron microscopy to visualize an ER lumen specific reporter in HeLa cells to make the initial observation that the autophagy-inducing condition of starvation causes an increase in ER-PM contact sites. Moreover, fluorescent microscopy studies show that autophagy specific markers colocalize with these contact sites, and newly formed autophagosomes are in the close vicinity. Causation experiments show that manipulation of ER-PM tethering proteins, extended synaptotagmin‐like proteins, E-syt1, E-syt2, and E-syt3, affect autophagosome initiation. During these experiments Nascimbeni and colleagues noted that phosphatidyl-inositol-3-phosphate (PI3P) was also localized at the ER-PM sites with the PM tethering proteins and hypothesized that E-syt1, E-syt2, and E-syt3 might be involved in PI3P synthesis. It has long been noted that the endoplasmic reticulum pool of PI3P is necessary for phagophore initiation and is synthesized by the core autophagy complexes comprised of VPS34, ATG14L, Beclin1, and ULK1/2 to name a few. However, for the first time Nascimbeni et al. showed that the ER-PM tethering proteins E-syt1, E-syt2, and E-syt3 are also essential for autophagy associated PI3P synthesis.
Immunocytochemistry/Immunofluorescence: E-syt1, FAM62A Antibody [NBP2-57412] - Staining of human cell line SiHa shows localization to the endoplasmic reticulum.
These are important findings in the field of autophagy as the source of phagophore membranes continues to be elucidated. One of the co-authors on the Nascimbeni et al. publication, Dr. Patrice Codogno spoke extensively about the implications of this work during a webinar at Novus Biologicals. Dr. Codogno is a research director at the French Institute for Health and Medical research and a long time contributing member to the field of autophagy. One of his noteworthy contributions, identified opposing roles of distinct classes of PI3-kinases and their roles in controlling the autophagic pathways. During this webinar, Dr. Codogno delves into the details of ER-PM tethering proteins and autophagosome biogenesis. Additionally, Dr. Codogno co-authored another recent publication in PNAS in 2017 that identified a protective role of autophagy in endothelial cells against atherosclerosis that is dependent on shear stress-induced autophagy7. In the recent webinar, he also highlights the implications of this work and the role that mechanical stress-induced autophagy may play in physiology and disease. Click below to take a listen.
Learn more about Autophagosome Biogenesis
Christina Towers, PhD
University of Colorado (AMC)
Dr. Towers studies the roles of autophagy, apoptosis and cell death in cancer.
References
