| RRC ID |
57983
|
| Author |
Ji CH, Kim HY, Heo AJ, Lee SH, Lee MJ, Kim SB, Srinivasrao G, Mun SR, Cha-Molstad H, Ciechanover A, Choi CY, Lee HG, Kim BY, Kwon YT.
|
| Title |
The N-Degron Pathway Mediates ER-phagy.
|
| Journal |
Mol Cell
|
| Abstract |
The endoplasmic reticulum (ER) is susceptible to wear-and-tear and proteotoxic stress, necessitating its turnover. Here, we show that the N-degron pathway mediates ER-phagy. This autophagic degradation initiates when the transmembrane E3 ligase TRIM13 (also known as RFP2) is ubiquitinated via the lysine 63 (K63) linkage. K63-ubiquitinated TRIM13 recruits p62 (also known as sequestosome-1), whose complex undergoes oligomerization. The oligomerization is induced when the ZZ domain of p62 is bound by the N-terminal arginine (Nt-Arg) of arginylated substrates. Upon activation by the Nt-Arg, oligomerized TRIM13-p62 complexes are separated along with the ER compartments and targeted to autophagosomes, leading to lysosomal degradation. When protein aggregates accumulate within the ER lumen, degradation-resistant autophagic cargoes are co-segregated by ER membranes for lysosomal degradation. We developed synthetic ligands to the p62 ZZ domain that enhance ER-phagy for ER protein quality control and alleviate ER stresses. Our results elucidate the biochemical mechanisms and pharmaceutical means that regulate ER homeostasis.
|
| Volume |
75(5)
|
| Pages |
1058-1072.e9
|
| Published |
2019-9-5
|
| DOI |
10.1016/j.molcel.2019.06.028
|
| PII |
S1097-2765(19)30485-X
|
| PMID |
31375263
|
| MeSH |
Animals
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Endoplasmic Reticulum / genetics
Endoplasmic Reticulum / metabolism*
HEK293 Cells
HeLa Cells
Humans
Mice
Mice, Knockout
Proteolysis*
Sequestosome-1 Protein / genetics
Sequestosome-1 Protein / metabolism*
Ubiquitination
|
| IF |
15.584
|
| Times Cited |
8
|
| Resource |
| Human and Animal Cells |
Atg5^(+/+)MEF(RCB2710)
Atg5^(-/-)MEF(RCB2711) |
