![]() ![]() We thus followed the fate of nonstop membrane proteins at the ER membrane with different membrane topologies, and found that the latter pathway is more important for the quality control of nonstop membrane proteins at the ER membrane. In the present study, we asked which of the pathways, the cytosolic Ltn1-dependent degradation and the Dom34-Hbs1 dependent release into the ER lumen, nonstop ER membrane proteins can be targeted to. Then, a question arises what the fate of nonstop organellar membrane proteins are, which contain a segment(s) exposed to the cytosol for possible ubiquitination by the cytosolic RQC pathway. The reason for such escape of certain nonstop organelle-targeted proteins from the cytosolic RQC pathway could be the limited exposure of the segments for cytosolic ubiquitination, although recent studies showed that such ubiquitination may take place under some conditions 14, 15. The cytosolic RQC pathway, which is important for the clearance of nonstop proteins in the cytosol, may not operate sufficiently for those nonstop proteins targeted to the ER and mitochondria. The Dom34-Hbs1 complex acts on the stalled ribosomes to release stuck nonstop proteins into the organelle lumen, and if this release does not work efficiently, the protein flux into the organelle is blocked, resulting in defective cell growth. Among them, we found that, when degradation of nonstop mRNAs does not work efficiently, nonstop proteins targeted to the ER or mitochondria occupy not only translating ribosomes but also translocons (translocators) in the organellar membranes 13. The nonstop cytosolic proteins are then ubiquitinated by Ltn1 (Listerin in mammals) associated with the RNC complex, and targeted to degradation by proteasomes 10, 11, 12.Īlthough degradation of nonstop cytosolic proteins has been extensively studied 1, 2, 3, fate of nonstop proteins targeted to organelles such as the endoplasmic reticulum (ER) and mitochondria was characterized only in a few studies 13, 14, 15. Entry of Hbs1-GTP into the A site of stalled ribosomes allows its GTP hydrolysis and induces a conformational change in Dom34, which leads to recruitment of the ATPase Rli1 (ABCE1 in mammals) to ribosomes for driving subunit dissociation and recycling of the ribosomal subunits 7, 8, 9. The stalled RNC complexes are split into the 60S large and 40S small subunits by the complex of Dom34 (Pelota in mammals) and Hbs1 6. In the yeast NSD pathway, exosome is recruited by the GTPase Ski7, which enters the A site of stalled ribosomes and interact with the Ski2-Ski3-Ski8 complex, and degrades the 5′ fragment of nonstop mRNA in the 3′–>5′ direction 1, 2, 3, 4, 5. Generation of stalled RNC complexes calls for the nonstop-decay (NSD) pathway to degrade nonstop mRNAs and ribosomal quality control (RQC) factors to deal with nonstop proteins and recycle the stalled ribosomes 1, 2, 3. mRNA lacking an in-frame stop codon called “nonstop mRNA” would generate aberrant “nonstop proteins” as well as accumulation of stalled ribosome-nascent chain (RNC) complexes. When detected, aberrant nascent chains are subjected to repair, yet terminally deteriorated polypeptide chains are targeted to disposal by cellular degradation systems. Aberrant proteins could be generated upon translation as well as after their synthesis. Proteins are under the elaborate surveillance to maintain cellular protein homeostasis. Therefore, the nascent chain release from the translation apparatus is more instrumental in clearance of the clogged ER translocon channel and thus maintenance of normal cellular functions. On the other hand, failure in the Dom34-dependent release of the nascent polypeptide from the ribosome led to the block of the Sec61 channel and resultant inhibition of other protein import into the ER caused cell growth defects. Ltn1-dependent degradation differed for membrane proteins with different topologies and its failure did not affect ER protein import or cell growth. Here we followed the fate of nonstop endoplasmic reticulum (ER) membrane proteins with different membrane topologies in yeast to evaluate the importance of the Ltn1-dependent cytosolic degradation and the Dom34-dependent release of the nonstop membrane proteins. the Sec61 complex) by release of nonstop proteins into the organellar lumen. Since messenger RNAs without a stop codon (nonstop mRNAs) for organelle-targeted proteins and their translation products (nonstop proteins) generate clogged translocon channels as well as stalled ribosomes, cells have mechanisms to degrade nonstop mRNAs and nonstop proteins and to clear the translocons (e.g. ![]()
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