SBK2

SBK2 (SH3 domain-binding kinase 2) is a muscle-specific, atrium-enriched serine/threonine protein kinase that maintains sarcomere integrity and restrains cardiac and inflammatory pathology through site-specific substrate phosphorylation (PMID:35587025, PMID:42153297). In atrial cardiomyocytes it localizes around the A-band of the sarcomere, and its loss disrupts sarcomeric organization and downregulates sarcomeric gene expression at both transcript and protein levels (PMID:35587025). SBK2 directly binds and phosphorylates the complex I subunit NDUFV1 at Ser251, which strengthens NDUFV1 association with the cytosolic chaperone HSPA1A and drives TOM70-dependent mitochondrial import; the resulting rise in mitochondrial NDUFV1 promotes complex I activity, respiratory supercomplex assembly, oxidative phosphorylation, and redox homeostasis, with cardiomyocyte SBK2 overexpression attenuating hypertrophy and a phospho-deficient NDUFV1-S251A mutant failing to rescue SBK2-deficient cells (PMID:42153297). In macrophages, SBK2 phosphorylates NLRP3 at Ser161 to trigger Tollip-dependent autophagic degradation of the inflammasome, and macrophage-specific SBK2 loss exacerbates atherosclerotic plaque formation while its activation suppresses IL-1β/IL-18 secretion (PMID:41684124).

1. 2022 Medium

   Established SBK2 as a sarcomere-associated cardiac kinase by showing it is required for atrial sarcomere structure, answering whether this kinase has a defined cellular role in cardiomyocytes.

   Evidence Knockdown in rat and human atrial myocytes with sarcomeric organization, transcriptome/proteome, immunofluorescence localization, and reciprocal Co-IP

   PMID:35587025

   Open questions at the time

   • No direct kinase substrate identified in this study
   • Co-IP partners were not validated as direct phosphorylation targets
   • Mechanism linking SBK2 to sarcomeric gene expression unresolved
2. 2026 High

   Identified NDUFV1-Ser251 as a direct SBK2 substrate, mechanistically connecting the kinase to mitochondrial complex I import and protection against cardiac hypertrophy.

   Evidence In vitro kinase assay with S251A mutagenesis, biochemical fractionation, blue native PAGE, and in vivo loss/gain-of-function with phospho-deficient rescue in mice

   PMID:42153297

   Open questions at the time

   • How SBK2 kinase activity itself is regulated is unknown
   • Whether the same axis operates outside cardiomyocytes is not addressed
   • Structural basis of NDUFV1 recognition not determined
3. 2026 High

   Extended SBK2 function to innate immunity by showing it phosphorylates NLRP3-Ser161 to drive Tollip-dependent autophagic inflammasome clearance, linking the kinase to atherosclerosis control.

   Evidence In vitro kinase assay, Co-IP, mass spectrometry, macrophage-specific KO/OE in mice, single-cell sequencing, and pharmacological rescue (rebaudioside N) abolished in KO

   PMID:41684124

   Open questions at the time

   • How Ser161 phosphorylation mechanistically recruits Tollip is not detailed
   • Relationship between the cardiac and macrophage SBK2 functions unexplored
   • Endogenous activator of SBK2 in macrophages unknown
4. 2026 Low

   Associated SBK2 with proteotoxic cardiac disease by documenting its downregulation in desmin-related cardiomyopathy models, raising the question of whether loss of SBK2 contributes to disease progression.

   Evidence RT-qPCR and western blotting in multiple DRC mouse models

   PMID:41653366

   Open questions at the time

   • Expression correlation only; no functional manipulation of SBK2 in this disease context
   • Causal contribution of SBK2 loss to DRC not tested
   • No substrate or pathway implicated in this model

• How SBK2 kinase activity is regulated upstream and how its sarcomeric, mitochondrial, and inflammasome functions are coordinated remain open.
• No upstream activator or signaling input identified
• No structural model of the kinase
• Unclear whether sarcomere maintenance is direct or downstream of metabolic effects