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. 2025 May 13;122(19):e2505345122.
doi: 10.1073/pnas.2505345122. Epub 2025 May 8.

Structural insights into the ubiquitin-independent midnolin-proteasome pathway

Nagesh Peddada  1 , Xue Zhong  1 , Yan Yin  1 , Danielle Renee Lazaro  1 , Jianhui Wang  1 , Stephen Lyon  1 , Jin Huk Choi  1 , Xiao-Chen Bai  2 , Eva Marie Y Moresco  1 , Bruce Beutler  1
Affiliations

Structural insights into the ubiquitin-independent midnolin-proteasome pathway

Nagesh Peddada et al. Proc Natl Acad Sci U S A. .

Abstract

The protein midnolin (MIDN) augments proteasome activity in lymphocytes and dramatically facilitates the survival and proliferation of B-lymphoid malignancies. MIDN binds both to proteasomes and to substrates, but the mode of interaction with the proteasome is unknown, and the mechanism by which MIDN facilitates substrate degradation in a ubiquitin-independent manner is incompletely understood. Here, we present cryoelectron microscopy (cryo-EM) structures of the substrate-engaged, MIDN-bound human proteasome in two conformational states. MIDN induces proteasome conformations similarly to ubiquitinated substrates by using its ubiquitin-like domain to bind to the deubiquitinase RPN11 (PSMD14). By simultaneously binding to RPN1 (PSMD2) with its C-terminal α-helix, MIDN positions its substrate-carrying Catch domain above the proteasome ATPase channel through which substrates are translocated before degradation. Our findings suggest that both ubiquitin-like domain and C-terminal α-helix must bind to the proteasome for MIDN to stimulate proteasome activity.

Keywords: MIDN; RPN1/PSMD2; RPN11/PSMD14; UBL domain; cryo-EM.

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Conflict of interest statement

Competing interests statement:The authors declare no competing interest.

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