TY - JOUR
T1 - Microtubule plus end-associated CLIP-170 initiates HSV-1 retrograde transport in primary human cells
AU - Jovasevic, Vladimir
AU - Naghavi, Mojgan H.
AU - Walsh, Derek
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health to M.H. Naghavi (R01GM101975 and P01GM105536) and D. Walsh (P01GM105536).
Publisher Copyright:
© 2015 Jovasevic et al.
PY - 2015/10/26
Y1 - 2015/10/26
N2 - Dynamic microtubules (MTs) continuously explore the intracellular environment and, through specialized plus end-tracking proteins (+TIPs), engage a variety of targets. However, the nature of cargoes that require +TIP-mediated capture for their movement on MTs remains poorly understood. Using RNA interference and dominant-negative approaches, combined with live cell imaging, we show that herpes simplex virus particles that have entered primary human cells exploit a +TIP complex comprising end-binding protein 1 (EB1), cytoplasmic linker protein 170 (CLIP-170), and dynactin-1 (DCTN1) to initiate retrograde transport. Depletion of these +TIPs completely blocked post-entry long-range transport of virus particles and suppressed infection ~5,000-fold, whereas transferrin uptake, early endosome organization, and dynein-dependent movement of lysosomes and mitochondria remained unaffected. These findings provide the first insights into the earliest stages of viral engagement of MTs through specific +TIPs, akin to receptors, with therapeutic implications, and identify herpesvirus particles as one of a very limited number of cargoes absolutely dependent on CLIP-170-mediated capture to initiate transport in primary human cells.
AB - Dynamic microtubules (MTs) continuously explore the intracellular environment and, through specialized plus end-tracking proteins (+TIPs), engage a variety of targets. However, the nature of cargoes that require +TIP-mediated capture for their movement on MTs remains poorly understood. Using RNA interference and dominant-negative approaches, combined with live cell imaging, we show that herpes simplex virus particles that have entered primary human cells exploit a +TIP complex comprising end-binding protein 1 (EB1), cytoplasmic linker protein 170 (CLIP-170), and dynactin-1 (DCTN1) to initiate retrograde transport. Depletion of these +TIPs completely blocked post-entry long-range transport of virus particles and suppressed infection ~5,000-fold, whereas transferrin uptake, early endosome organization, and dynein-dependent movement of lysosomes and mitochondria remained unaffected. These findings provide the first insights into the earliest stages of viral engagement of MTs through specific +TIPs, akin to receptors, with therapeutic implications, and identify herpesvirus particles as one of a very limited number of cargoes absolutely dependent on CLIP-170-mediated capture to initiate transport in primary human cells.
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U2 - 10.1083/jcb.201505123
DO - 10.1083/jcb.201505123
M3 - Article
C2 - 26504169
AN - SCOPUS:84971322252
VL - 211
SP - 323
EP - 337
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 2
ER -