Small but Powerful: The Human Vault RNAs as Multifaceted Modulators of Pro-Survival Characteristics and Tumorigenesis.

The importance of non-coding RNAs for regulating gene expression has been uncovered in model systems spanning all three domains of life. More recently, their involvement in modulating signal transduction, cell proliferation, tumorigenesis and cancer progression has also made them promising tools and targets for oncotherapy. Recent studies revealed a class of highly conserved small ncRNAs, namely vault RNAs, as regulators of several cellular homeostasis mechanisms. The human genome encodes four vault RNA paralogs that share significant sequence and structural similarities, yet they seem to possess distinct roles in mammalian cells. The alteration of vault RNA expression levels has frequently been observed in cancer tissues, thus hinting at a putative role in orchestrating pro-survival characteristics. Over the last decade, significant advances have been achieved in clarifying the relationship between vault RNA and cellular mechanisms involved in cancer development. It became increasingly clear that vault RNAs are involved in controlling apoptosis, lysosome biogenesis and function, as well as autophagy in several malignant cell lines, most likely by modulating signaling pathways (e.g., the pro-survival MAPK cascade). In this review, we discuss the identified and known functions of the human vault RNAs in the context of cell proliferation, tumorigenesis and chemotherapy resistance.

Deleting key autophagy elongation proteins induces acquirement of tumor-associated phenotypes via ISG15.

Autophagy is a cellular catabolic process that maintains intracellular homeostasis using lysosomal degradation systems. We demonstrate that inhibiting autophagy by depleting essential autophagy elongation proteins, Atg5 or Atg7, induces ISG15 expression through STING-mediated cytosolic dsDNA response. Genome stability is impaired in ATG5- or ATG7-depleted cells, and thus, double-strand breakages of DNA increase and cytosolic dsDNA accumulates. Accumulated cytosolic dsDNA induces the STING pathway to activate type I IFN signals which induce STAT1 activity and downregulate ATF3. When depletion of ATG5 or ATG7 inhibits autophagy, ATF3 is downregulated and STAT1 is upregulated. Furthermore, inhibiting autophagy induces ISG15 expression through STAT1 activation, which promotes acquisition of tumor-associated phenotypes such as migration, invasion, and proliferation. In conclusion, it appears that via the STING-mediated cytosolic dsDNA response, the STAT1-ISG15 axis mediates the relationship between autophagy and the immune system in relation to tumor progression. Moreover, combined with autophagy control, regulating ISG15 expression could be a novel strategy for cancer immunotherapy.

JNK activation induced by ribotoxic stress is initiated from 80S monosomes but not polysomes.

Translation is a costly, but inevitable, cell maintenance process. To reduce unnecessary ATP consumption in cells, a fine-tuning mechanism is needed for both ribosome biogenesis and translation. Previous studies have suggested that the ribosome functions as a hub for many cellular signals such as ribotoxic stress response, mammalian target of rapamycin (mTOR), and ribosomal S6 kinase (RSK) signaling. Therefore, we investigated the relationship between ribosomes and mitogen-activated protein kinase (MAPK) activation under ribotoxic stress conditions and found that the activation of c-Jun N-terminal kinases (JNKs) was suppressed by ribosomal protein knockdown but that of p38 was not. In addition, we found that JNK activation is driven by the association of inactive JNK in the 80S monosomes rather than the polysomes. Overall, these data suggest that the activation of JNKs by ribotoxic stress is attributable to 80S monosomes. These 80S monosomes are active ribosomes that are ready to initiate protein translation, rather than polysomes that are already acting ribosomes involved in translation elongation. [BMB Reports 2019; 52(8): 502-507].

RACK1 depletion in the ribosome induces selective translation for non-canonical autophagy.

RACK1, which was first demonstrated as a substrate of PKCß II, functions as a scaffold protein and associates with the 40S small ribosomal subunit. According to previous reports, ribosomal RACK1 was also suggested to control translation depending on the status in translating ribosome. We here show that RACK1 knockdown induces autophagy independent of upstream canonical factors such as Beclin1, Atg7 and Atg5/12 conjugates. We further report that RACK1 knockdown induces the association of mRNAs of LC3 and Bcl-xL with polysomes, indicating increased translation of these proteins. Therefore, we propose that the RACK1 depletion-induced autophagy is distinct from canonical autophagy. Finally, we confirm that cells expressing mutant RACK1 (RACK1R36D/K38E) defective in ribosome binding showed the same result as RACK1-knockdown cells. Altogether, our data clearly show that the depletion of ribosomal RACK1 alters the capacity of the ribosome to translate specific mRNAs, resulting in selective translation of mRNAs of genes for non-canonical autophagy induction.