2. Academic Validation
  3. PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly

PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly

  • Mol Cell. 2023 Nov 16;83(22):4123-4140.e12. doi: 10.1016/j.molcel.2023.09.028.
Ming-Chieh Chou 1,  Yi-Hsuan Wang 1,  Fei-Yun Chen 2,  Chun-Ying Kung 1,  Kuen-Phon Wu 1,  Jean-Cheng Kuo 3,  Shu-Jou Chan 2,  Mei-Ling Cheng 4,  Chih-Yu Lin 5,  Yu-Chi Chou 6,  Meng-Chiao Ho 1,  Steven Firestine 7,  Jie-Rong Huang 3,  Ruey-Hwa Chen 8
Affiliations

Affiliations

  • 1 Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
  • 2 Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
  • 3 Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
  • 4 Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan.
  • 5 Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan.
  • 6 Biomedical Translation Research Center, Academia Sinica, Taipei 115, Taiwan.
  • 7 Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
  • 8 Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan. Electronic address: rhchen@gate.sinica.edu.tw.
PMID: 37848033 DOI: 10.1016/j.molcel.2023.09.028
Abstract

Purinosomes serve as metabolons to enhance de novo purine synthesis (DNPS) efficiency through compartmentalizing DNPS Enzymes during stressed conditions. However, the mechanism underpinning purinosome assembly and its pathophysiological functions remains elusive. Here, we show that K6-polyubiquitination of the DNPS enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) by cullin-5/ankyrin repeat and SOCS box containing 11 (Cul5/ASB11)-based ubiquitin Ligase plays a driving role in purinosome assembly. Upon several purinosome-inducing cues, ASB11 is upregulated by relieving the H3K9me3/HP1α-mediated transcriptional silencing, thus stimulating PAICS polyubiquitination. The polyubiquitinated PAICS recruits ubiquitin-associated protein 2 (UBAP2), a ubiquitin-binding protein with multiple stretches of intrinsically disordered regions, thereby inducing phase separation to trigger purinosome assembly for enhancing DNPS pathway flux. In human melanoma, ASB11 is highly expressed to facilitate a constitutive purinosome formation to which melanoma cells are addicted for supporting their proliferation, viability, and tumorigenesis in a xenograft model. Our study identifies a driving mechanism for purinosome assembly in response to cellular stresses and uncovers the impact of purinosome formation on human malignancies.

Keywords

Cullin-RING ubiquitin ligase; biomolecular condensates; de novo purine synthesis; liquid-liquid phase separation; metabolon; purinosome; ubiquitination.

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