Age-related noncanonical TRMT6–TRMT61A signaling impairs hematopoietic stem cells

Aged hematopoietic stem cells (HSCs) exhibit compromised reconstitution capacity and differentiation bias toward myeloid lineages. However, the molecular mechanism behind HSC aging remains largely unknown. In this study, we observed that RNA N1-methyladenosine-generating methyltransferase TRMT6–TRMT61A complex is increased in aged murine HSCs due to aging-declined CRL4DCAF1-mediated ubiquitination degradation signaling. Unexpectedly, no difference of tRNA N1-methyladenosine methylome is observed between young and aged hematopoietic stem and progenitor cells, suggesting a noncanonical role of the TRMT6–TRMT61A complex in the HSC aging process. Further investigation revealed that enforced TRMT6–TRMT61A impairs HSCs through 3′-tiRNA-Leu-CAG and subsequent RIPK1–RIPK3–MLKL-mediated necroptosis cascade. Deficiency of necroptosis ameliorates the self-renewal capacity of HSCs and counters the physiologically deleterious effect of enforced TRMT6–TRMT61A on HSCs. Together, our work uncovers a nonclassical role for the TRMT6–TRMT61A complex in HSC aging and highlights a therapeutic target. He et al. demonstrate a noncanonical role for the TRMT6–TRMT61A methyltransferase complex in hematopoietic stem cell (HSC) aging, where its enrichment activates necroptosis signaling. Blocking necroptosis counters features of HSC aging, suggesting a therapeutic strategy.