Sánchez-Álvarez, MiguelLolo, Fidel NicolásSailem, HebaFulgoni, GiulioPascual-Vargas, PatriciaAgüera, LucíaCatalá-Montoro, MauroArias-García, MarLópez, Juan AntonioVázquez, JesúsDel Pozo, Miguel ÁngelBakal, Chris2025-07-022025-07-022025-05-27Cell Rep. 2025 May 27;44(5):115590.https://hdl.handle.net/20.500.12105/26798Light microscopy and dynamic imaging/ICTS-ReDib at CNIC is supported by MCIN/AEI/10.13039/501100011033 and FEDER ‘‘Una manera de hacer Europa’’ (#ICTS-2018-04-CNIC-16; Madrid, Spain). Amine Sadok and Faraz Mardakheh (former researchers at ICR, London, UK) provided expert advice and assistance with collagen migration experiments. C.B. and H.S. have been beneficiaries of the Wellcome Trust Career Development Fellowship program. Funding support at the C.B. lab was received from the Cancer Research UK (CRUK) Programme Foundation Award (C37275/A20146) and the Stand Up to Cancer campaign. M.S.-A. was a fellow of the COFUND-IPP program (CNIC); is a recipient of grants from the Spanish Ministerio de Ciencia e Innovacio´ n (MICINN; RYC2020-029690-I and PID2021-128106NA-I00) and the Scientific Foundation, Spanish Association Against Cancer (LAB AECC 2024 grant LABAE246690SANC); and is supported by consolidation grant CNS2023-144831, sponsored by Ministerio de Ciencia, Innovacio´ n y Universidades (MICIU)/AEI/10.13039/501100011033 and European Union NextGenerationEU/PRTR. The M.A.d.P. lab is sponsored by Spanish Ministerio de Ciencia e Innovacio´ n (MCNU; PID2020-118658RB-I00, SAF2017-83130-R, and BFU2016-81912-REDC); the Comunidad Autónoma de Madrid/FEDER, Spain (ref. S2018/NMT4443; Actividades de I+D entre Grupos de Investigación en Tecnologías); Obra Social La Caixa (AtheroConvergence-HR20-00075); and the Fundacio´ la Marato´ de TV3 (385/C/2019). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovacio´ n y Universidades (MICIU), and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIU/AEI/10.13039/501100011033). The M.S-A. laboratory is a member of the RERCSIC rare disease research network.The architecture of the endoplasmic reticulum (ER) is a key determinant of its function. Its dynamics are linked to those of the cytoskeleton, but our understanding of how this coordination occurs and what its functional relevance is, limited. Here, we report that the unfolded protein response (UPR) transducer EIF2AK3/PERK (eukaryotic translation initiation factor 2-alpha kinase 3/protein kinase R-like endoplasmic reticulum kinase) is essential for acute-stress-induced peripheral redistribution and remodeling of the ER through eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation and translation initiation shutdown. PERK-mediated eIF2α phosphorylation can be bypassed by blocking polysome assembly, depleting microtubule (MT)-anchoring ER proteins such as p180/RRBP1 (ribosome-binding protein 1), or disrupting the MT cytoskeleton. Specific disruption of non-centrosomal MTs, but not centrosome depletion, rescues ER redistribution in PERK-deficient cells. Conversely, PERK deficiency stabilizes non-centrosomal MTs against proteasomal degradation, promoting polarized protrusiveness in epithelial cells and neuroblasts. Thus, PERK coordinates ER architecture and homeostasis with cell morphogenesis by coupling ER remodeling and non-centrosomal MT stability and dynamics.engVoRhttp://creativecommons.org/licenses/by/4.0/CP: Cell biologyEIF2AK3/PERKcell polarityendoplasmic reticulumintegrated stress responsenon-centrosomal microtubulesAttribution 4.0 International40267909Cell Reportsopen access