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TitleMolecular mechanism of HUWE1-HAPSTR1-USP7-mediated ubiquitin chain amplification on nuclear proteins.
Journal, issue, pagesMol Cell, Vol. 86, Issue 18, Page 3803-3821.e17, Year 2026
Publish dateSep 17, 2026
AuthorsStanislau Yatskevich / Jugal Mohapatra / Rana Mroue / Lilian Phu / Alexander Leitner / Caleigh M Azumaya / Richard Vandlen / Tommy K Cheung / Tik Hang Soong / Christopher M Rose / Alessandro Ori / Claudio Ciferri / Szymon Juszkiewicz /
PubMed AbstractRapid protein turnover is essential for cellular stress adaptation. HUWE1 (HECT, UBA, and WWE domain containing 1), a large HECT-type E3 ligase, regulates many short-lived stress-responsive proteins, ...Rapid protein turnover is essential for cellular stress adaptation. HUWE1 (HECT, UBA, and WWE domain containing 1), a large HECT-type E3 ligase, regulates many short-lived stress-responsive proteins, yet the mechanisms underlying its substrate selectivity remain unclear. Here, we reveal that HUWE1 functions as a ubiquitin chain amplifier that captures pre-ubiquitinated substrates and amplifies the degradation signal by assembling long ubiquitin chains containing K11-K48 branch points, a process regulated by its partners HUWE1-associated protein stress response 1 (HAPSTR1) and USP7 (ubiquitin-specific-processing protease 7). Structural and biochemical analyses show that HAPSTR1 engages HUWE1's ubiquitin-binding motifs to drive nuclear import and modulate substrate recruitment. A cryo-EM structure of the HUWE1-USP7 complex reveals a bidirectional regulatory mechanism: HUWE1 activates USP7's catalytic activity, while USP7 modulates HUWE1 conformational states. Global proteomic analyses demonstrate that this axis drives extensive remodeling of the short-lived nuclear proteome. These findings establish the HUWE1-HAPSTR1-USP7 complex as a key ubiquitin code modifier, providing a molecular rationale for HUWE1 dysregulation in neurodevelopmental disorders and cancer.
External linksMol Cell / PubMed:42753704
MethodsEM (single particle)
Resolution2.8 - 3.6 Å
Structure data

71720

9plq

EMDB-71720, PDB-9plq:
HUWE1(CS)-Ubiquitin bound to the HECT domain
Method: EM (single particle) / Resolution: 3.19 Å

71721

9plr

EMDB-71721, PDB-9plr:
CryoEM reconstruction of HUWE1-USP7 complex in the closed state
Method: EM (single particle) / Resolution: 2.88 Å

EMDB-72134: HUWE1-Ub consensus refinement map
Method: EM (single particle) / Resolution: 3.19 Å

EMDB-72135: HUWE1-Ub local refinement on HECT domain
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-72139: Consensus HUWE1-USP7 refinement
Method: EM (single particle) / Resolution: 2.88 Å

EMDB-72140: HUWE1-USP7 local refinement, with focus on US7 catalytic domain
Method: EM (single particle) / Resolution: 3.18 Å

EMDB-72141: HUWE1-USP7 local refinement, focusing on USP7 Ubl1,2 domains
Method: EM (single particle) / Resolution: 2.93 Å

EMDB-72142: HUWE1-USP7 local refinement, with focus on USP7 Ubl4,5 domains
Method: EM (single particle) / Resolution: 2.8 Å

Source
  • homo sapiens (human)
KeywordsLIGASE / Ubiquitin complex / HUWE1 / E3 ligase / Complex / E3-ligase-DUB

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