ER‐to‐lysosome‐associated degradation in a nutshell: mammalian, yeast, and plant ER‐phagy as induced by misfolded proteins

Abstract

Conserved catabolic pathways operate to remove aberrant polypeptides from the endoplasmic reticulum (ER), the major biosynthetic organelle of eukaryotic cells. The best known are the ER‐associated degradation (ERAD) pathways that control the retrotranslocation of terminally misfolded proteins across the ER membrane for clearance by the cytoplasmic ubiquitin/proteasome system. In this review, we catalog folding‐defective mammalian, yeast, and plant proteins that fail to engage ERAD machineries. We describe that they rather segregate in ER subdomains that eventually vesiculate. These ER‐derived vesicles are captured by double membrane autophagosomes, engulfed by endolysosomes/vacuoles, or fused with degradative organelles to clear cells from their toxic cargo. These client‐specific, mechanistically diverse ER‐phagy pathways are grouped under the umbrella term of ER‐to‐lysosome‐associated degradation for description in this essay.

Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease

“…These results are in line with the fact that if chaperone-mediated folding cannot rescue misfolding, proteasomal degradation occurs since UPS is the main ER quality control mechanism (Lim & Yue, 2015). However, UPS can degrade misfolded proteins generated in the ER via ERAD, whereas ER portions containing ERAD-resistant misfolded proteins (e.g., aggregates) are mainly cleared by ERLAD (Rudinskiy & Molinari, 2023).…”

Hypoxia stabilizes the H2O2‐producing oxidase Nox4 in cardiomyocytes via suppressing autophagy‐related lysosomal degradation

“…In cells treated with bafilomycin A1 and chloroquine, both of which block autophagy via inhibiting autophagosome maturation and lysosomal degradation (Wang et al, 2019), the amount of Nox4 protein was increased (Figure 5e,f). Taken together, the ER protein Nox4 appears to be degraded in cardiomyocytes via an autophagy‐related pathway, which is currently recognized as ER‐to‐lysosome‐associated degradation (ERLAD) (Rudinskiy & Molinari, 2023).…”

“…In the present study, we show that hypoxia increases Nox4‐catalyzed H 2 O 2 production in H9c2 cardiomyocytes (Figure 1). The increase is regulated not at the transcriptional level but at the posttranslational level (Figure 2), probably via the hypoxia‐induced suppression of the autophagy‐related lysosomal degradation, that is, ERLAD (Rudinskiy & Molinari, 2023), of Nox4 (Figure 5). The control of Nox4 abundance at the protein level in hypoxic cardiomyocytes is in sharp contrast to that in other types of cells such as endothelial and smooth muscle cells, where Nox4 is upregulated at the mRNA level by the hypoxia‐induced transcription factor HIF‐1 (Craige et al, 2011; Diebold et al, 2010; Mittal et al, 2007; Wang et al, 2014) (Figure 2).…”

“…However, it remains presently unknown how hypoxia suppresses the lysosomal degradation of Nox4. The delivery of Nox4 to the lysosome might be mediated by the ER chaperone calnexin, because this protein interacts well with Nox4 (Prior, Leisegang, et al, 2016; Prior, Wittig, et al, 2016) and participates in entry of client proteins to the ERLAD pathway (Rudinskiy & Molinari, 2023).…”

“…In these cells, Nox4 is stabilized at the protein level under hypoxic conditions, which stabilization requires the presence of p22 phox . Intriguingly, Nox4 is degraded in cardiomyocytes not via the proteasome pathway but probably via an autophagy‐related pathway, that is, ER‐to‐lysosome‐associated degradation (ERLAD) (Rudinskiy & Molinari, 2023), which is likely suppressed in response to hypoxia, leading to stabilization of Nox4.…”