2026/07/27 by Haishan Tan, Yuxiang Hu, Qinglan Wang
paper · doi:10.1128/jb.00221-26
ABSTRACT Mammalian cell entry (Mce) systems are now recognized as central determinants of lipid uptake, cell-envelope homeostasis, and host adaptation in Mycobacterium tuberculosis (Mtb). Although the term “mammalian cell entry” originated from early studies linking the Mce loci to host-cell invasion phenotypes, subsequent genetic, biochemical, and structural work has substantially reframed their biological significance. Current evidence supports a model in which Mce1 and Mce4 function as multiprotein lipid-import systems specialized primarily for fatty-acid and cholesterol uptake, respectively, whereas shared and accessory factors, including MceG, LucA, Mam/Omam proteins, and the negative regulator Mce1N, govern transporter assembly, stability, and activity. At the same time, several individual Mce proteins have been implicated in host signaling and immunomodulation, although the physiological relevance of these observations remains unevenly established. In this review, we synthesize current knowledge of Mtb Mce systems with an emphasis on transporter organization, regulatory mechanisms, functional specialization, and biological significance during infection. We further discuss evolutionary relationships with other Mce-domain proteins, assess the strength of evidence supporting reported host-interaction phenotypes, and evaluate the translational potential of Mce biology for diagnostics, vaccines, and drug discovery. By emphasizing recent structural and regulatory breakthroughs, this review repositions Mce biology from a historically entry-centered narrative toward a transporter-centered, evidence-graded framework and highlights the key unresolved questions that should guide the next phase of the field, including substrate-level specificity, native structural validation, and the mechanistic integration of lipid transport with metabolism and virulence.