Ktd1 is a phospho-regulated member of the Dup240 family that mediates defence against killer toxin K28

Newly identified TRAF7 interacts with TAK1 and regulates immune response in Chlamys farreri.

This study provides a new perspective for understanding the evolutionary conservation and species specificity of molluscan innate immune signaling pathways and offers important theoretical support for further comprehension of the molecular mechanism of scallop immune defense and promoting the green control of aquatic diseases in marine farming.

CcFTR54 suppresses SVCV replication by promoting NBR1-mediated autophagic degradation of P protein.

The tripartite motif-containing (TRIM) protein family is crucial for antiviral innate immunity. In teleost, finTRIM proteins (FTRs) represent a fish-specific TRIM subfamily that underwent extensive lineage-specific expansion. Nevertheless, the biological roles of many FTR members have yet to be fully deciphered. Here, we identified common carp finTRIM54 (CcFTR54) as potent restriction factor against spring viremia of carp virus (SVCV) infection by targeting the viral phosphoprotein (P). CcFTR54 overexpression significantly rescued the type I interferon (IFN-I) signaling from SVCV P-mediated suppression. Mechanistic investigations revealed that CcFTR54 directly bond to P protein via its PRY/SPRY domain, enhancing the recruitment of the cargo receptor NBR1 to the P protein. Consequently, NBR1 deficiency substantially attenuated both CcFTR54-mediated P protein degradation and its antiviral efficacy. Furthermore, CcFTR54 catalyzes K6- and K33-linked ubiquitination of P protein at K205, a site crucial for SVCV replication. Together, our findings unveil a novel mechanism where CcFTR54 restricts SVCV replication via NBR1-dependent selective autophagic degradation of the viral P protein, thereby broadening our insights into finTRIM-mediated antiviral immunity in teleosts.

A Regulatory Element in the Intrinsically Disordered C-Terminal Region of LMTK3 Modulates Its Kinase Domain Interactions and Breast Cancer Phenotypes

Lemur tail kinase 3 (LMTK3) is an oncogenic Ser/Thr kinase implicated in breast cancer (BC) progression, therapy resistance, and poor clinical outcomes, yet the molecular mechanisms governing its regulation remain poorly understood, particularly the role of its C-terminal intrinsically disordered region (IDR). Given that IDRs frequently harbour hidden structural motifs that control protein dynamics, we combined computational, biophysical, and biochemical approaches to systematically map regulatory elements within the LMTK3 C-terminus, identifying two regions (residues 688–1095 and 1181–1486) that interact with the LMTK3 kinase domain (LMTK3-KD). Characterisation of these interactions revealed that LMTK31181–1486 displays preferential binding to inactive wild-type LMTK3-KD over a constitutively active mutant (LMTK3-KDL313R), a behaviour consistent with a potential autoinhibitory interaction. Guided by AlphaFold3 modelling, we localised this interaction primarily to a short α-helical motif (α-helix 2; residues 1247–1258) within the C-terminal IDR and subsequently identified Ser1258 within this motif as a candidate regulatory phosphorylation site, using [γ-32P]-ATP kinase assays and mass spectrometry. Phosphorylation at Ser1258 altered interactions between α-helix 2 and the kinase domain, reducing binding to wild-type LMTK3-KD while increasing affinity for LMTK3-KDL313R. Functionally, phospho-null mutation of Ser1258 impaired oestrogen receptor alpha (ERα) upregulation, proliferation, migration, and clonogenicity in ER-positive BC cell lines, and reduced tumour growth in female BALB/c nude mice bearing orthotopic MCF7 xenografts. Together, these findings identify a previously uncharacterised regulatory element within the LMTK3 C-terminus and support a model in which Ser1258 phosphorylation modulates kinase domain interactions and LMTK3-driven oncogenic functions in BC.

Linker domain Ser-phosphorylation as a putative modulator for ABCB alkaloid transporters

Structural similarities within the linker domain of different ABCB-type proteins revealed structural similarities within the linker domain, including the presence of [R/K-X-S/T] and [R/K-X-X-S/T] motifs, which are potential phosphorylation sites for kinases of the AGCVIII superfamily, and a phosphorylation-based regulatory mechanism is proposed for ABCB alkaloid transporters.

Identification of a Ubiquitin-Independent Degron by a Reporter Assay.

The zinc metalloprotease ZMPSTE24 binds a distinct topological isoform of the tail-anchored protein IFITM3.

The biogenesis of integral membrane proteins is complex, as revealed by an ever-growing number of cellular components dedicated to the insertion, folding, surveillance, rectification, or quality control of specific client membrane proteins. The zinc metalloprotease ZMPSTE24 and its yeast homolog Ste24 have well-established roles in the proteolytic maturation of the nuclear scaffold protein lamin A and yeast a-factor, respectively. Additionally, Ste24 has been implicated through yeast genetic screens in a variety of membrane processes, including ER- associated degradation (ERAD), Sec61 translocon "unclogging," and potentially as a membrane protein topology determinant. Recently, an interaction was demonstrated between ZMPSTE24 and the antiviral interferon induced transmembrane protein IFITM3, although the functional significance of this interaction is poorly understood. IFITM3 is a tail-anchored protein with a cytoplasmic N-terminus, a single transmembrane span, and a lumenal/exocellular C-terminus. Here, we show that a catalytic-dead version of ZMPSTE24, ZMPSTE24E336A, exhibits enhanced binding to IFITM3, and this bound species of IFITM3 is hypo-palmitoylated. Using a split fluorescence topology reporter, we demonstrate that ZMPSTE24E336A "traps" and stabilizes a subpopulation of IFITM3 molecules with an atypical membrane topology, whose C-terminus is cytosolic instead of lumenal. Such inverted forms of IFITM3 are also detected in the presence of ERAD inhibitors or for a lysineless version of IFITM3. We hypothesize the ZMPSTE24E336A trap mutant reveals a normally transient isoform of IFITM3 whose transmembrane span is inverted and that ZMPSTE24 is involved in the quality control of IFITM3 topology, either inverting, correcting or assisting in removal of aberrant IFITM3 molecules.