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ER-phagy: the lysosomal control of endoplasmic reticulum homeostasis



Molinari M.



The endoplasmic reticulum (ER) is the site of proteins, lipids and oligosaccharides biogenesis, detoxification of harmful macromolecules, calcium storage in nucleated cells. ER size and functions are rapidly adapted to cellular needs upon activation of anabolic unfolded protein responses (UPRs), or of catabolic ER-phagy responses.

UPRs enlarge the ER and increase its content in biosynthetic enzymes, molecular chaperones and degradation factors upon activation of pathways that are understood in such molecular details, that UPRs modulators already entered the clinics/clinical trials as therapeutic agents for a series of human diseases caused by ER dysfunction.

ER-phagy removes ER portions in response to pleiotropic signals that activate multiple ER-phagy receptors (e.g., nutrient restriction), or in response to ER-centric signals that activate individual ER-phagy receptors (e.g., recovery from ER stress, accumulation of protein aggregates, ribosome stalling). ER-phagy responses are defective in neurological/motor disorders and various types of cancer and are hijacked by human pathogens. Their better characterization is instrumental to develop pharmacologic modulators of these catabolic pathways that maintain, in co-ordination with UPRs, ER homeostasis and function.

ER-phagy receptors are membrane-bound proteins (FAM134 family, SEC62, TEX264, RTN3L, CCPG1, ATL3), or cytosolic proteins recruited at the ER membrane upon activation (CALCOCO1, C53, p62). They display at least one LIR (LC3-interacting region), a short linear sequence that engages cytosolic Atg8/LC3/GABARAP proteins. For membrane-bound ER-phagy receptors, the LIR is placed within a cytosolic intrinsically disordered region (IDR), which is proposed to bridge the space between the portion of the ER that must be cleared from the cell and the phagophore or the endolysosome that will engulf it. Activation of ER-phagy receptors promotes fragmentation of the organelle and delivery of ER-portions to the degradative vacuolar or endolysosomal compartments for clearance. According to current models, the membrane curvature induced by reticulum homology domains (RHD) characterizing the membrane anchoring of FAM134B plays a crucial role in the ER fragmentation that drives ER-phagy. However, it should be mentioned that RHDs are absent in most ER-phagy receptors identified so far in Eukarya and in receptors for autophagy of other organelles that also relies on fragmentation (e.g., mitochondria).

Our research activity will focus on 3 receptors, FAM134B, SEC62 and TEX264, which are characterized by different tethering to the ER membrane (RHDs for FAM134B, and conventional double, and single spanning transmembrane domains for SEC62 and TEX264, respectively). FAM134B and TEX264 control starvation-induced ER-phagy (Dikic’s, Mizushima’s and Harper’s groups). Moreover, with the ER lectin chaperone Calnexin, FAM134B ensures autophagic degradation of ER subdomains containing disease-causing aberrant gene products (e.g., collagen and alpha1-antitrypsin mutants, our group). SEC62-driven ER-phagy restores the size and activity of the ER and the ultrastructure of the nuclear envelope, during recovery from acute ER stresses (our group).

The selection of these receptors is based on the fact that we have generated a series of reagents including knock out cells and cells expressing endogenously tagged versions of the receptors (CRISPR/Cas9 genome editing), plasmids for expression of the ER-phagy receptors tagged with a series of fluorescent and non-fluorescent epitopes (including the tandem Halo-GFP tag developed in our lab for colorimetric monitoring of proteins and organelle delivery within endolysosomes).

The 4-years study supported by the FNS will allow us to hopefully elucidate

i) Signal-specific ER-phagy receptor(s) activation.

ii) ER-phagy receptor-driven ER fragmentation and delivery to the endolysosomal compartments.

iii) Endolysosomal responses to ER-phagy activation.

Informazioni aggiuntive

Data d'inizio
Data di fine
48 Mesi
Enti finanziatori
In corso
Swiss National Science Foundation / Project Funding / Life Sciences (Division III)