Abstract
Thirty percent of all cellular proteins are inserted into the endoplasmic reticulum (ER), which spans throughout the cytoplasm. Two well-established stress-induced pathways ensure quality control (QC) at the ER: ER-phagy and ER-associated degradation (ERAD), which shuttle cargo for degradation to the lysosome and proteasome, respectively. In contrast, not much is known about constitutive ER-phagy. We have previously reported that excess of integral-membrane proteins is delivered from the ER to the lysosome via autophagy during normal growth of yeast cells. Whereas endogenously expressed ER resident proteins serve as cargos at a basal level, this level can be induced by overexpression of membrane proteins that are not ER residents. Here, we characterize this pathway as constitutive ER-phagy. Constitutive and stress-induced ER-phagy share the basic macro-autophagy machinery including the conserved Atgs and Ypt1 GTPase. However, induction of stress-induced autophagy is not needed for constitutive ER-phagy to occur. Moreover, the selective receptors needed for starvation-induced ER-phagy, Atg39 and Atg40, are not required for constitutive ER-phagy and neither these receptors nor their cargos are delivered through it to the vacuole. As for ERAD, while constitutive ER-phagy recognizes cargo different from that recognized by ERAD, these two ER-QC pathways can partially substitute for each other. Because accumulation of membrane proteins is associated with disease, and constitutive ER-phagy players are conserved from yeast to mammalian cells, this process could be critical for human health.
Highlights
The endoplasmic reticulum (ER) is the first stop for ~30% of all cellular proteins and as such is subject to a number of quality control (ER-QC) mechanisms [1]
We have previously shown that excess integralmembrane proteins are cleared from the ER by macro-autophagy during normal growth of yeast cells
We identified two different proteins that upon overexpression serve as cargos for this pathway: GFP-Snc1-PEM and Snq2-yEGFP; Snc1 is a v-SNARE with a single trans-membrane domain (TMD) that mediates fusion of Golgi vesicles with the plasma membrane (PM), and Snq2 is a multi-TMD ABC transporter
Summary
The endoplasmic reticulum (ER) is the first stop for ~30% of all cellular proteins and as such is subject to a number of quality control (ER-QC) mechanisms [1]. The two destinations for excess or damaged cellular components are the proteasome and the lysosome. ER-associated degradation (ERAD) delivers misfolded proteins from the ER to the proteasome, especially during ER stress [2]. ER fragments containing membrane and proteins can be delivered to the lysosome via micro- or macro-autophagy. In micro-autophagy, cellular components are enwrapped directly by the lysosomal membrane, while in macro-autophagy, they are first engulfed by the double-membrane autophagosome (AP), which later fuses with the lysosomal membrane. Macro-autophagy is induced by nutritional stress and requires a set of conserved autophagy-related proteins, Atgs [3,4]. There is a constitutive macro-autophagy pathway that during normal growth delivers proteins from the cytoplasm to the vacuole (the yeast lysosome), CVT [6]. Knowledge about constitutive macro-autophagy in general is scarce in yeast and human cells
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