TRIM13 (tripartite motif-containing 13) improves mitophagy of dendritic cells via promoting SESN2 (sestrin 2)-induced K63-linked ubiquitination in sepsis

Sepsis constitutes a life-threatening organ dysfunction caused by a dysregulated host response to infection. SESN2 (sestrin 2), an evolutionarily conserved stress-responsive protein, is a pivotal regulator of cellular homeostasis. Here, we identified TRIM13 (tripartite motif-containing 13) as a regulator that modulated the stability of SESN2 at the post-translational level. Specifically, TRIM13 promoted K63-linked ubiquitination of SESN2 with subsequent upregulation of its functional activation. Ubiquitinated SESN2 initiated a selective macroautophagic/autophagic program that facilitated the recruitment of SQSTM1/p62 (sequestosome 1/p62) to mitochondrial surfaces. The enhanced interaction between ubiquitinated SESN2 and the mitophagy receptor FUNDC1 (FUN14 domain-containing 1) at mitochondria-associated membranes (MAMs), facilitated by this modification, potentiated the mitophagic clearance of damaged mitochondria. In addition, it inhibited the interaction between FUNDC1 and RIPK3 (receptor-interacting serine-threonine kinase 3), which in turn ameliorated dysfunction and necroptosis of dendritic cells (DCs) upon sepsis. Thus, our findings establish that TRIM13 mitigates septic responses by activating SESN2-mediated mitophagy through ubiquitination, offering new insights into potential immunomodulatory strategies for sepsis. Abbreviations: AF: AlphaFold; BECN1: beclin 1, autophagy related; CLP: cecal ligation and puncture; co-IP: co-immunoprecipitation; DAMPs: danger/damageassociated molecular patterns; DCs: dendritic cells; DEGs: differentially expressed genes; FUNDC1: FUN14 domain containing 1; IL: interleukin; LPS: lipopolysaccharide; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MHC: major histocompatibility complex; MLKL: mixed lineage kinase domain-like; Nec-1: necrostatin-1; PBMCs: peripheral blood mononuclear cells; RIPK3: receptor-interacting serine-threonine kinase 3; SESN2: sestrin 2; SIRT1: sirtuin 1; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TLR: toll-like receptor; TNF: tumor necrosis factor; TRAF6: TNF receptor-associated factor 6; TRIM13: tripartite motif-containing 13; ULK1: unc-51 like kinase 1; UPR: unfolded protein response; UPS: ubiquitinproteasome system; WT: wild-type.