The function of SMYD5 (SMYD family member 5, Ensembl gene identifier ENSG00000135632) is as follows. Protein-lysine N-trimethyltransferase that specifically catalyzes trimethylation of 'Lys-22' of the RPL40/eL40 subunit of the 60S ribosome, thereby promoting translation elongation and protein synthesis (PubMed:39048817, PubMed:39103523). May also act as a histone methyltransferase in the context of histone octamers, but not on nucleosome substrates: trimethylates 'Lys-36' of histone H3 and 'Lys- 20' of histone H4 to form H3K36me3 and H4K20me3, respectively (By similarity). The histone methyltransferase activity, which is independent of its SET domain, is however unsure in vivo (PubMed:39048817, PubMed:39103523). In association with the NCoR corepressor complex, involved in the repression of toll-like receptor 4 (TLR4)-target inflammatory genes in macrophages, possibly by catalyzing the formation of H4K20me3 at the gene promoters (By similarity). Plays an important role in embryonic stem (ES) cell self-renewal and differentiation (By similarity). Maintains genome stability of ES cells during differentiation through regulation of heterochromatin formation and repression of endogenous repetitive DNA elements by promoting H4K20me3 marks (PubMed:28951459). Acts as a regulator of the hypothermia response: its degradation in response to mild hypothermia relieves the formation of H3K36me3 at gene promoters, allowing expression of the neuroprotective gene SP1 (By similarity). {ECO:0000250|UniProtKB:Q3TYX3, ECO:0000269|PubMed:28951459, ECO:0000269|PubMed:39048817, ECO:0000269|PubMed:39103523}.