HEATR3 is a HEAT repeat-containing protein with dual roles in ribosome biogenesis and selective autophagy. Primarily, HEATR3 functions as a nuclear import factor essential for transporting ribosomal proteins uL5 (RPL5) and uL18 (RPL11) into the nucleus, facilitating large ribosomal subunit assembly and erythrocyte maturation 1. The protein contains an LC3-interacting region enabling recognition of cytoplasmic bacterial pathogens and damaged membranes, directing them to autolysosomes for degradation through selective autophagy 2. Additionally, HEATR3 serves as a nuclear import adaptor for the Legionella effector Ceg10 3. Biallelic HEATR3 variants cause Diamond-Blackfan anemia (DBA-21), characterized by impaired nuclear import of uL18, defective pre-rRNA processing, and accelerated but defective erythroid maturation independent of p53 activation 1. HEATR3 dysfunction disrupts ribosome biogenesis across multiple cell types. Beyond hematologic disease, HEATR3 expression variants associate with increased uterine fibroid risk 45, elevated Crohn's disease susceptibility in Ashkenazi Jewish populations through NOD2-mediated NF-κB signaling 6, and potentially mycobacterial infection susceptibility 7. In HER2-positive breast cancer, HEATR3 upregulation promotes progression via LMAN2 interaction and Akt/ERK/NF-κB pathway activation 8. These findings establish HEATR3 as a multifunctional protein critical for ribosomal protein homeostasis, innate immunity, and disease pathogenesis.