The Lederkremer Lab
The Shmunis School of Biomedicine and Cancer Research
The George S. Wise Faculty of Life Sciences
Tel Aviv University
Mechanisms and sub-cellular compartmentalization of endoplasmic reticulum (ER) quality control and ERAD.
The ER-derived quality control compartment (ERQC).
Endoplasmic reticulum-associated degradation (ERAD) of a misfolded glycoprotein in mammalian cells requires the removal of 3–4 alpha 1,2 linked mannose residues from its N-glycans. The trimming and recognition processes are ascribed to ER Mannosidase I, the ER-degradation enhancing mannosidase-like proteins (EDEMs), and the lectins OS-9 and XTP3-B, all residing in the ER, the ER-derived quality control compartment (ERQC), or quality control vesicles (QCVs). Folded glycoproteins with untrimmed glycans are transported from the ER to the Golgi complex, where they are substrates of other alpha 1,2 mannosidases, IA, IB, and IC. The apparent redundancy of these enzymes has been puzzling for many years. We have now determined that, surprisingly, mannosidase IA is not located in the Golgi but resides in QCVs. We had recently described this type of vesicles, which carry ER α1,2 mannosidase I (ERManI). We show that the overexpression of alpha class I α1,2 mannosidase IA (ManIA) significantly enhances the degradation of ERAD substrates and its knockdown stabilizes it. Our results indicate that ManIA trims mannose residues from Man9GlcNAc2 down to Man5GlcNAc2, acting in parallel with ERManI and the EDEMs, and targeting misfolded glycoproteins to ERAD.
https://www.sciencedirect.com/science/article/pii/S0022283616300791?via%3Dihub#f0035
Sugar chain trimming processes as signals for folding status and quality control of glycoproteins
The ability of mammalian cells to correctly identify and degrade misfolded secretory proteins, most of them bearing N-glycans, is crucial for their correct function and survival. An inefficient disposal mechanism results in the accumulation of misfolded proteins and consequent endoplasmic reticulum (ER) stress. N-glycan processing creates a code that reveals the folding status of each molecule, enabling continued folding attempts or targeting of the doomed glycoprotein for disposal. We review here the main steps involved in the accurate processing of unfolded glycoproteins. We highlight recent data suggesting that the processing is not stochastic, but that there is selective accelerated glycan trimming on misfolded glycoprotein molecules.
https://www.sciencedirect.com/science/article/pii/S0968000419300921?via%3Dihub
Delivery of misfolded proteins to ER-associated degradation (ERAD)
Misfolded proteins and components of the endoplasmic reticulum (ER) quality control and ER associated degradation (ERAD) machineries concentrate in mammalian cells in the pericentriolar ER-derived quality control compartment (ERQC), suggesting it as a staging ground for ERAD. By tracking the chaperone calreticulin and an ERAD substrate, we have now determined that the trafficking to the ERQC is reversible and recycling back to the ER is slower than the movement in the ER periphery. The dynamics suggest vesicular trafficking rather than diffusion. Indeed, using dominant negative mutants of ARF1 and Sar1 or the drugs Brefeldin A and H89, we observed that COPI inhibition causes accumulation in the ERQC and increases ERAD, whereas COPII inhibition has the opposite effect. Our results suggest that targeting of misfolded proteins to ERAD involves COPII-dependent transport to the ERQC and that they can be retrieved to the peripheral ER in a COPI-dependent manner.
https://www.sciencedirect.com/science/article/pii/S2589004223003097?via%3Dihub
ER stress in neurodegeneration
Protein aggregation is a common feature of the protein misfolding or conformational diseases, among them most of the neurodegenerative diseases. These disorders are a major scourge, with scarce if any effective therapies at present. Recent research has identified ER stress as a major mechanism implicated in cytotoxicity in these diseases. Whether amyloid-β or tau in Alzheimer's, α-synuclein in Parkinson's, huntingtin in Huntington's disease or other aggregation-prone proteins in many other neurodegenerative diseases, there is a shared pathway of oligomerization and aggregation into amyloid fibrils. There is increasing evidence in recent years that the toxic species, and those that evoke ER stress, are the intermediate oligomeric forms and not the final amyloid aggregates. This review focuses on recent findings on the mechanisms and importance of the development of ER stress upon protein aggregation, especially in neurodegenerative diseases, and possible therapeutic approaches that are being examined.
https://www.sciencedirect.com/science/article/pii/S0006899316301834?via%3Dihub
Neurodegenerative diseases and other protein misfolding diseases (Huntington’s, Alzheimer’s, etc.)
"Researchers have long believed that Huntington’s disease results from a mutation that causes a protein called Htt to become abnormally sticky and form toxic clusters, or “aggregates,” in neurons. Targeting these protein aggregates has become the primary focus of newly developed pharmaceutical therapies. But according to Lederkremer and Leitman’s research, these drug treatments may not only be ineffective — they may actually pose a serious threat to patients.
In two innovative studies, published in the journals PLOS ONE and Nature Communications, Lederkremer and his team demonstrated that protein clusters are not the cause of brain cell damage in Huntington’s disease. On the contrary, these agents actually serve as a defense mechanism for “stressed” brain cells. By using cutting-edge microscopic technology on tissue cultures, their studies identified a different causative agent — the “stress response” of affected brain cells."
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From a No Camels article.