DDX3 regulates diverse translation responses. Three regional divisions of mRNA are shown from left to right, 5’ UTR, CDS, and 3’ UTR as well as the 5’ cap and the poly(A) tail. (A) Normal translation. DDX3 (blue-filled circles) binds preferentially to the 5’ UTR and complicated secondary structures (pin-shaped dark gray lines). DDX3 promotes mostly translation initiation in the 5’UTR and also elongation in the CDS. (B). Either DDX3 in cells under stress or catalytically compromised DDX3 (red-filled circles) represses translation at the initiation and the elongation stages, resulting not only in the accumulation of secondary structures (pin-shaped dark gray lines) and but also in translation initiations from uORFs (yellow box) (e.g., ATF4; note the blue line from an uORF-associated ribosome). Ribosome stalling due to induced secondary structures can also increase the level of cotranslationally ubiquitinated nascent polypeptides (red line attached to the ribosome). (C) Stress induces stress granules (SGs) of ribonucleoprotein complex via complexation of translation-unengaged mRNAs and translation initiation factors with DDX3. Under SG-forming conditions, DDX3 binding spreads to the CDS and the 3’ UTR (note the spread of the red-filled circles to the CDS and the 3’ UTR). While most of the translation is halted, some privileged mRNAs, e.g., histone mRNAs, still undergo translation.