The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. Ataxin-2-like (ATXN2L) is preferentially nuclear, more abundant, essential for embryonic life, and its sequestration into ATXN2 aggregates might contribute to disease. Here, two approaches elucidated ATXN2L roles. We identified (i) interactors by coimmunoprecipitation in wildtype and ATXN2L-null murine embryonic fibroblasts, (ii) proteome profile effects by mass spectrometry in these cells, (iii) ATXN2L interactor accumulation in the SCA2 mouse model Atxn2-CAG100-KnockIn (KIN). We observed RNA-binding proteins PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL to show mostly stronger association with ATXN2L than established interactors (ATXN2, PABPC1, LSM12, and G3BP2). ATXN2L also interacted with actin complex components SYNE2, LMOD1, ACTA2, FYB and GOLGA3. Oxidative stress increased HNRNPK but decreased SYNE2 association, likely reflecting SG relocalization. Among these interactors, proteome profiling revealed NUFIP2 and SYNE2 as depleted in ATXN2L-null fibroblasts. NUFIP2 homodimers and SYNE1 accumulated during the ATXN2 aggregation process in KIN 14-month-old spinal cords. Overall, the functions of ATXN2L and its interactors are important in RNA granule trafficking and surveillance, particularly for differentiated neuron maintenance