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Membrane localization of HspA1A, a stress inducible 70‐kDa heat shock protein, is mediated by the lipid phosphatidylserine

Seventy‐kilodalton heat shock proteins (Hsp70s) are molecular chaperones essential for regulating cellular homeostasis. Apart from their indispensable roles in protein homeostasis, specific Hsp70s, including HspA1A, also localize at the plasma membrane (PM) of 90% of human and mouse tumors and its PM presence has been associated with bad patient prognosis. However, it is currently unknown how HspA1A, a protein that lacks membrane localization signals, is translocated and anchored to the PM. We have recently demonstrated that HspA1A interacts with several lipids, including phosphatidylserine (PS), a lipid found primarily in the inner leaflet of the PM during normal cell growth. Taking into account that lipids recruit proteins to the PM, we hypothesized that the interaction of HspA1A with PS allows the chaperone to localize at the PM. To test this hypothesis, we determined the translocation pattern of HspA1A in three human cell lines and also whether the C2 domain of lactadherin (Lact‐C2), a known PS‐biosensor, inhibits this translocation. Specifically, cells were subjected to mild heat‐shock, a condition that does not induce apoptosis, and the PM‐localized HspA1A was quantified using confocal microscopy and cell surface biotinylation. These experiments revealed that in the absence of Lact‐C2, HspA1A's membrane localization increases during recovery from non‐apoptotic heat‐shock and this phenomenon is unrelated to PM‐charge. In the presence of Lact‐C2, however, HspA1A's membrane localization is inhibited. Furthermore, we used TopFluor‐PS, a fluorescent PS analog, and established that it co‐localizes with HspA1A. Collectively, these results strongly suggest that HspA1A's membrane localization, anchorage, and embedding depends on its interaction with intracellular PS. This discovery institutes PS as a new and dynamic partner in the cellular stress response and establish the foundation to directly assess the biological implications of this newly described function of Hsp70s.