Biology subjects

Schroth, S.

Publications and source records attributed to Schroth, S..

2 recordsLinked to original sources

bioRxiv2026

Chaperone structure is not a sufficient determinant for the hierarchy of substrate secretion in bacterial type III secretion systems

Functional type III secretion in Gram negative bacteria relies on precise substrate targeting and a strict order of secretion with early, intermediate, and late substrates. Type III secretion chaperones facilitate these processes by maintaining substrates in a partially unfolded, secretion-competent state and serving as order-specific targeting factors. Early needle filament assembling substrates are chaperoned by none or class III chaperones, intermediate translocator-type substrates by class II and late effector-type substrates by class I chaperones. In case of hydrophobic transmembrane effectors, chaperones may also serve to prevent erroneous mistargeting of these substrates to the bacterial inner membrane. Here, we characterized the Salmonella transmembrane effectors SseF and SseG and their chaperone SscB, encoded in the operon sscB-sseF-sseG, in order to gain a deeper understanding of the underlying molecular requirements of targeting of this special class of substrates. We show that the gene linkage of SscB and SseF is critical for these proteins stability and SseF secretion. Counterintuitively, SscB revealed to feature a class II chaperone structure with a class I chaperone function. Likewise, SseF and SseG harbour conserved, translocator-like chaperone-binding motifs (PXI/LXXP) but were secreted as late substrates, independent of the gatekeeper protein SsaL. These findings challenge the current chaperone classification and our understanding of the molecular basis of the hierarchy of substrate secretion. They show that chaperone structure is not a sufficient molecular determinant for the correct order of substrate secretion.

microbiology↗

bioRxiv2021

Bone Marrow-Derived AXL Tyrosine Kinase Promotes Mitogenic Crosstalk and Cardiac Allograft Vasculopathy

Cardiac Allograft Vasculopathy (CAV) is a leading contributor to late transplant rejection. Although implicated, the mechanisms by which bone marrow-derived cells promote CAV remain unclear. Emerging evidence implicates the cell surface receptor tyrosine kinase AXL to be elevated in rejecting human allografts. AXL protein is found on multiple cell types, including bone marrow-derived myeloid cells. The causal role of AXL from this compartment and during transplant is largely unknown. This is important because AXL is a key regulator of myeloid inflammation. Utilizing experimental chimeras deficient in the bone marrow-derived Axl gene, we report that Axl antagonizes cardiac allograft survival and promotes CAV. Flow cytometric and histologic analyses of Axl-deficient transplant recipients revealed reductions in both allograft immune cell accumulation and vascular intimal thickness. Co-culture experiments designed to identify cell-intrinsic functions of Axl uncovered complementary cell-proliferative pathways by which Axl promotes CAV-associated inflammation. Specifically, Axl-deficient myeloid cells were less efficient at increasing the replication of both antigen-specific T cells and vascular smooth muscle cells (VSMCs), the latter a key hallmark of CAV. For the latter, we discovered that Axl-was required to amass the VSMC mitogen Platelet-Derived Growth Factor. Taken together, our studies reveal a new role for myeloid Axl in the progression of CAV and mitogenic crosstalk. Inhibition of AXL-protein, in combination with current standards of care, is a candidate strategy to prolong cardiac allograft survival.

immunology↗