The ubiquitin ligase Cullin5^SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation

Area of Science:

• Biochemistry
• Molecular Biology
• Immunology

Background:

• Suppressor of Cytokine Signaling 2 (SOCS2) is an E3 ligase implicated in inflammation and growth, but its substrates and functions remain largely unknown.
• Understanding SOCS2's targets is crucial for elucidating its role in inflammatory diseases and potential oncogenic pathways.

Purpose of the Study:

• To identify novel protein substrates of SOCS2 using proteomic profiling.
• To investigate the functional consequences of SOCS2-mediated regulation of its newly identified target, NDR1.
• To explore the role of the SOCS2-NDR1 axis in inflammatory responses and prostate cancer.

Main Methods:

• Proteomic profiling via mass spectrometry to identify SOCS2-interacting proteins after SOCS2 depletion.
• Biochemical assays to confirm SOCS2-NDR1 interaction and ubiquitination.
• Functional studies using cell-based assays and a SOCS2 knockout mouse model of colitis.

Main Results:

• Proteomic screening identified NDR1 (a serine-threonine kinase) as a novel substrate of SOCS2.
• SOCS2 directly interacts with NDR1, promoting its degradation via K48-linked ubiquitination.
• SOCS2 antagonizes NDR1-induced TNFα-stimulated NF-κB activity, and NDR1 depletion rescues SOCS2-deficiency effects.
• SOCS2 deficiency in mice correlates with increased inflammation, lower NDR1, and reduced nuclear p65 levels.
• NDR1 shows potential oncogenic activity in prostate cancer.

Conclusions:

• SOCS2 targets NDR1 for degradation, providing a mechanistic link between SOCS2 deficiency and hyperactivated NF-κB signaling.
• The SOCS2-mediated degradation of NDR1 acts as a critical switch to restrict the TNFα-NF-κB pathway.
• This pathway is relevant to inflammatory conditions like colitis and potentially oncogenesis in prostate cancer.