LRRC41

LRRC41 (MUF1) is a leucine-rich repeat, BC-box-containing protein that functions as a substrate-recognition subunit of Cullin-RING E3 ubiquitin ligase complexes (PMID:11384984). It assembles with Elongin BC, Cul5, and Rbx1 to reconstitute ubiquitin ligase activity in vitro (PMID:11384984), and coimmunoprecipitates with CUL5 in bone marrow cells, where CUL5 controls LRRC41 protein levels downstream of IL-3 signaling (PMID:40569692). As the substrate receptor of a CRL2-type ligase, LRRC41 ubiquitinates DDX5 in a non-degradative manner that promotes DDX5 binding to ELAVL1 and stabilizes Noggin (NOG) mRNA, supporting spermatogonial stem cell-like proliferation and migration (PMID:40775760), and it ubiquitinates HNRNPC via K63 linkage to activate the NF-κB pathway in hepatocellular carcinoma cells (PMID:41942610). LRRC41 is itself a regulated substrate: it is degraded by the proteasome through the RhoBTB3-Cul3 ligase complex, being the first identified substrate of RhoBTB-Cul3 ligases (PMID:22709582), while the deubiquitinase USP7 opposes this turnover and stabilizes LRRC41 (PMID:41942610). The protein is predominantly nuclear and capable of homodimerization, relocating partially to the cytoplasm upon coexpression with RhoBTB proteins (PMID:22709582).

1. 2001 High

   Established LRRC41/MUF1 as an active E3 ligase component rather than an uncharacterized LRR protein, defining its core biochemical role as a substrate-recognition subunit of a Cul5-based ligase.

   Evidence Protein purification from rat liver with in vitro reconstitution of ubiquitin ligase activity and BC-box motif identification

   PMID:11384984

   Open questions at the time

   • No physiological substrate identified at this stage
   • Cellular context and regulation of the ligase unknown
2. 2012 Medium

   Showed that LRRC41 is itself a target of ubiquitin-mediated turnover, identifying RhoBTB3-Cul3 as the responsible ligase and placing LRRC41 within a regulatory feedback of the ubiquitin system.

   Evidence Yeast two-hybrid, reciprocal Co-IP, localization imaging, proteasome inhibitor and dominant-negative Cul3 stability assays

   PMID:22709582

   Open questions at the time

   • Functional consequence of RhoBTB-driven degradation on CRL5 activity not resolved
   • Homodimerization rests on a single Co-IP
   • Mechanism of cytoplasmic relocation upon RhoBTB coexpression unclear
3. 2025 Medium

   Connected LRRC41-CUL5 assembly to physiological signaling by showing CUL5 regulates LRRC41 (and STAT5) levels in hematopoietic stem cells downstream of IL-3.

   Evidence Reciprocal Co-IP in bone marrow cells, Cul5 conditional knockout mouse, HSPC proteomics

   PMID:40569692

   Open questions at the time

   • Direct ubiquitination substrate within this axis not defined
   • Whether LRRC41 acts as receptor or passive substrate here unclear
4. 2025 Medium

   Identified the first direct substrate of CRL2-LRRC41 (DDX5) and a non-degradative ubiquitination outcome linking the ligase to RNA-binding-protein function and mRNA stability.

   Evidence Knockdown, proteomic substrate ID, Co-IP, ubiquitination and proliferation/migration assays in spermatogonial stem cell-like cells

   PMID:40775760

   Open questions at the time

   • Ubiquitin linkage type on DDX5 not defined
   • Whether CRL2 versus CRL5 scaffold is used not reconciled with earlier Cul5 evidence
   • Single cell-type context
5. 2026 Medium

   Defined a stabilization-then-signaling axis in which USP7 deubiquitinates LRRC41 and LRRC41 in turn drives K63-linked ubiquitination of HNRNPC to activate NF-κB.

   Evidence IP-MS, Co-IP, ubiquitination assays, in vitro functional assays and xenograft models in hepatocellular carcinoma

   PMID:41942610

   Open questions at the time

   • Mechanism by which K63-ubiquitinated HNRNPC activates NF-κB not detailed
   • Generality beyond hepatocellular carcinoma untested

• How LRRC41 partitions between CRL5 and CRL2 scaffolds and what determines its choice of degradative versus non-degradative ubiquitination across substrates remains unresolved.
• No structural model of substrate engagement
• Cullin scaffold selection rules unknown
• Full substrate repertoire uncharacterized