TIM-family Proteins Promote Infection of Multiple Enveloped Viruses through Virion-associated Phosphatidylserine

Jemielity, Stephanie; Wang, Jinyize J.; Chan, Ying Kai; Ahmed, Asim A.; Li, Wenhui; Monahan, Sheena; Bu, Xia; Farzan, Michael; Freeman, Gordon J.; Umetsu, Dale T.; DeKruyff, Rosemarie H.; Choe, Hyeryun

The TIM protein family is composed of three members in humans (hTIM1, 3, and 4) and eight in mice (mTIM1-8) that are implicated in the regulation of innate and adaptive immune responses [18] . Based on expression, functional and structural data hTIM1, 3, and 4 are considered direct orthologs of mTIM1, 3, and 4, respectively [19, 20] . The ectodomain of TIM proteins includes an N-terminal variable immunoglobulin-like (IgV) domain and a stalk-like mucin domain that varies in length and O-glycosylation [18] . Importantly, the IgV domains of all hTIM proteins contain a high-affinity binding site for PS, a phospholipid constituent of eukaryotic membranes [21, 22] . Generally present on the cytosolic side of the plasma membrane lipid bilayer, PS flips to the outer leaflet upon the onset of apoptosis, where it acts as a so-called ''eat-me'' signal for professional phagocytes (macrophages and dendritic cells) as well as non-professional phagocytes (e.g., epithelial cells) [23] [24] [25] . Consistent with a PS receptor function, one important role of TIM proteins is to initiate PS-mediated engulfment of apoptotic cells and debris [21, 22, 26] . Although this role may be more prominent for TIM3 and TIM4, which are expressed on dendritic cell and macrophage sub-populations [21, 22, 26, 27] , TIM1 is known to be expressed on various epithelial cells [5, 28] , which can also assume phagocytic roles. TIM1 and TIM3 are further expressed on subsets of activated Tcells, where they act as costimulatory and coinhibitory molecules, respectively [29] [30] [31] .