2. Academic Validation
  3. A LisH-domain protein interaction map reveals a Lis1-ARIH2-dynein regulatory axis

A LisH-domain protein interaction map reveals a Lis1-ARIH2-dynein regulatory axis

  • iScience. 2025 Oct 30;28(11):113912. doi: 10.1016/j.isci.2025.113912.
Devanshi Gupta 1 2,  Subbareddy Maddika 1
Affiliations

Affiliations

  • 1 Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Uppal, Hyderabad, Telangana 500039, India.
  • 2 Graduate Studies, Regional Centre for Biotechnology, Faridabad, Haryana 121001, India.
PMID: 41312386 DOI: 10.1016/j.isci.2025.113912
Abstract

LisH-domain-containing proteins are involved in diverse cellular processes and disease mechanisms, yet their functional interaction landscape remains poorly characterized. Here, we employed a proteomics-based strategy to systematically map the interaction network of 27 LisH-domain-containing proteins, uncovering 1,410 high-confidence interactions-90% of which are previously unreported. This network reveals unanticipated roles for LisH proteins in cellular regulation and uncovers links to human disease, including cancer-associated interactions. Focusing on Lis1, a cytoplasmic dynein regulator, we identify the RBR-E3 ubiquitin Ligase ARIH2 as a key functional interactor. We show that Lis1 promotes ARIH2 deneddylation via the COP9 signalosome (CSN), modulating its ubiquitin Ligase activity. Active, neddylated ARIH2 ubiquitinates dynein intermediate chain 1 (DIC1), thus facilitating dynein function in proper organelle positioning. Our findings provide a comprehensive LisH protein interaction network and uncover a regulatory axis involving Lis1-ARIH2 that is important for dynein dependent intracellular transport.

Keywords

Biochemistry; Proteomics.

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