Polyglutamine homorepeat regulates Runx2 condensation and cellular localization in a KPNA3-dependent manner

  • Cell Rep. 2026 Mar 27;45(4):117205. doi: 10.1016/j.celrep.2026.117205.
Jia Hui Weng  1 ,  Shui Bo Xu  2 ,  Jia Chen Lv  1 ,  Yu Yao Li  3 ,  Hua Chen  4 ,  Ting Rui Zhang  1 ,  Hao Di Liang  1 ,  Rui Jie Chen  1 ,  Lin Chen  4 ,  Xiao Chen  1 ,  Hongwei Ouyang  1 ,  Li Ling Zheng  5 ,  Weiliang Shen  6 ,  Li Dong Wu  7 ,  Yi Ting Zhou  8
Affiliations
  • 1. Department of Orthopaedic Surgery of the Second Affiliated Hospital and Department of Biochemistry, Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 310058, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 2. Department of Orthopaedic Surgery of the Second Affiliated Hospital and Department of Biochemistry, Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 310058, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: [email protected].
  • 3. School of Basic Medical Sciences, Henan University, Kaifeng 475004, China.
  • 4. Center of Bone Metabolism and Repair, Laboratory of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Daping Hospital, Army Medical University, Chongqing 400042, China.
  • 5. Department of Orthopaedic Surgery of the Second Affiliated Hospital and Department of Biochemistry, Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 310058, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Hangzhou 310000, China.
  • 6. Department of Orthopaedic Surgery of the Second Affiliated Hospital and Department of Biochemistry, Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 310058, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: [email protected].
  • 7. Department of Orthopaedic Surgery of the Second Affiliated Hospital and Department of Biochemistry, Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: [email protected].
  • 8. Department of Orthopaedic Surgery of the Second Affiliated Hospital and Department of Biochemistry, Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 310058, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Hangzhou 310000, China. Electronic address: [email protected].
PMID: 41903133 DOI: 10.1016/j.celrep.2026.117205
Abstract

Homorepeat sequences are abundant in proteomes, and their expansion or deletion is linked to neurodegenerative and developmental diseases. RUNX2, a master regulator of osteogenesis, contains a unique polyglutamine (polyQ) and polyalanine (polyA) tandem domain (QA). Here, we show that the deletion of polyQ, but not polyA, induces RUNX2 aggregation in the cytoplasm. KPNA3/importin α4 specifically governs RUNX2 nuclear import and condensation, and its depletion inhibits osteoblast differentiation. We find that an intrinsically disordered region (IDR) adjacent to the nuclear localization sequence (NLS) drives RUNX2 condensation. Structural modeling indicates that polyQ deletion causes folding of the remaining N terminus, including the polyA region, thereby blocking KPNA3 access to the NLS. Low bone mineral density-associated deletion mutations in polyQ impair the Runx2-KPNA3 interaction, leading to aberrant cytoplasmic aggregation. These results unveil a unique role for the polyQ repeat in sustaining KPNA3 interaction, which is essential for RUNX2 nuclear import and maintaining its liquid-like condensate state.

Keywords
CP: cell biology; CP: developmental biology; Cleidocranial dysplasia; Karyopherin; Runx2; homorepeat; importin; osteogenesis; phase separation; polyQ repeat; “steric hindrance” model.
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